4-Pyrrolidino-phenyl-benzyl ether derivatives

ABSTRACT

The invention relates to racemic or enantiomerically pure 4-pyrrolidino derivatives, processes for their preparation, pharmaceutical compositions comprising said derivatives, and their use in the prevention and treatment of illness, in particular which is mediated by monoamine oxidase B inhibitors, in particular Alzheimer&#39;s disease or senile dementia.

FIELD OF THE INVENTION

[0001] The present invention relates to new 4-pyrrolidino derivatives,to processes and intermediates for their preparation, and topharmaceutical compositions containing them. These compounds areselective monoamine oxidase B inhibitors and, therefore, are useful fortreating or preventing diseases mediated by monoamine oxidase B.

BACKGROUND OF THE INVENTION

[0002] Monoamine oxidase (MAO, EC 1.4.3.4) is a flavin-containing enzymeresponsible for the oxidative deamination of endogenous monoamineneurotransmitters such as dopamine, serotonin, adrenaline, ornoradrenaline, and trace amines, e.g. phenylethyl-amine, as well as anumber of amine xenobiotics. The enzyme exists in two forms, MAO-A andMAO-B, encoded by different genes [Bach et al., Proc. Natl. Acad. Sci.USA 85:4934-4938 (1988)] and differing in tissue distribution, structureand substrate specificity. MAO-A has higher affinity for serotonin,octopamine, adrenaline, and noradrenaline; whereas the naturalsubstrates for MAO-B are phenylethylamine and tyramine. Dopamine isthought to be oxidised by both isoforms. MAO-B is widely distributed inseveral organs including brain [Cesura and Pletscher, Prog. DrugResearch 38:171-297 (1992)]. Brain MAO-B activity appears to increasewith age. This increase has been attributed to the gliosis associatedwith aging [Fowler et al., J. Neural. Transm. 49:1-20 (1980)].Additionally, MAO-B activity is significantly higher in the brains ofpatients with Alzheimer's disease [Dostert et al., Biochem. Pharmacol.38:555-561 (1989)] and it has been found to be highly expressed inastrocytes around senile plaques [Saura et al., Neuroscience 70:755-774(1994)]. In this context, since oxidative deamination of primarymonoamines by MAO produces NH₃, aldehydes and H₂O₂, agents withestablished or potential toxicity, it is suggested that there is arationale for the use of selective MAO-B inhibitors for the treatment ofdementia and Parkinson's disease. Inhibition of MAO-B causes a reductionin the enzymatic inactivation of dopamine and thus prolongation of theavailability of the neurotransmitter in dopaminergic neurons. Thedegeneration processes associated with age and Alzheimer's andParkinson's diseases may also be attributed to oxidative stress due toincreased MAO activity and consequent increased formation of H₂O₂ byMAO-B.

[0003] Therefore, MAO-B inhibitors may act by both reducing theformation of oxygen radicals and elevating the levels of monoamines inthe brain.

[0004] Given the implication of MAO-B in the neurological disordersmentioned above, there is considerable interest to obtain potent andselective inhibitors that would permit control over this enzymaticactivity. The pharmacology of some known MAO-B inhibitors is for examplediscussed by Bentué-Ferrer et al. [CNS Drugs 6:217-236 (1996)]. Whereasa major limitation of irreversible and non-selective MAO inhibitoractivity is the need to observe dietary precautions due to the risk ofinducing a hypertensive crisis when dietary tyramine is ingested, aswell as the potential for interactions with other medications [Gardneret al., J. Clin. Psychiatry 57:99-104 (1996)], these adverse events areof less concern with reversible and selective MAO inhibitors, inparticular of MAO-B. Thus, there is a need for MAO-B inhibitors with ahigh selectivity and without the adverse side-effects typical ofirreversible MAO inhibitors with low selectivity for the enzyme.

SUMMARY OF THE INVENTION

[0005] The invention relates to racemic or enantiomerically pure4-pyrrolidino derivatives, processes for their preparation,pharmaceutical compositions comprising said derivatives, and their usein the prevention and treatment of illness. More particularly, thepresent invention relates to compounds of the formula I

[0006] wherein Q is ═N— or ═C(R²⁴)—; X—Y is —CH₂—CH₂—, —CH═CH— or—CH₂—O—; and R¹, R^(1.1), R^(1.2), R³, R⁴, R²¹, R²², R²³, and R²⁴ are asdefined herein. The invention includes individual isomers of thecompounds herein as well as racemic and non-racemic mixtures thereof.

[0007] It has been found that the compounds of general formula I and I*as well as individual isomers, racemic or non-racemic mixtures thereof(hereinafter: Active Compounds) are selective monoamine oxidase Binhibitors. Therefore, the invention relates to pharmaceuticalcompositions and methods for treating diseases mediated by MAO-Binhibitors, for example, Alzheimer's disease and senile dementia.

DETAILED DESCRIPTION OF THE INVENTION

[0008] The following definitions of general terms used herein applyirrespective of whether the terms in question appear alone or incombination. It must be noted that, as used in the specification and theappended claims, the singular forms “a”, “an,” and “the” include pluralforms unless the context clearly dictates otherwise.

[0009] The term “individual isomers, racemic or non-racemic mixturesthereof” denotes E- and Z-isomers, mixtures thereof as well asindividual configurational isomers and mixtures thereof.

[0010] The term “(C₁-C₆)-alkyl” used in the present application denotesstraight-chain or branched saturated hydrocarbon residues with 1 to 6carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl,sec-butyl, t-butyl, and the like, preferably with 1 to 3 carbon atoms.Accordingly, the term “(C₁-C₃)-alkyl” means a straight-chain or branchedsaturated hydrocarbon residue with 1 to 3 carbon atoms.

[0011] “(C₁-C₆)-Alkoxy” means the residue —O—R, wherein R is a loweralkyl residue as defined herein. Examples of alkoxy radicals include,but are not limited to, methoxy, ethoxy, isopropoxy, and the like.

[0012] The term “halogen” denotes fluorine, chlorine, bromine andiodine.

[0013] “Halogen-(C₁-C₆)-alkyl” or “halogen-(C₁-C₆)-alkoxy” means thelower alkyl residue or lower alkoxy residue, respectively, as definedherein substituted in any position with one or more halogen atoms asdefined herein. Examples of halogenalkyl residues include, but are notlimited to, 1,2-difluoropropyl, 1,2-dichloropropyl, trifluoromethyl,2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, and 3,3,3-trifluoropropyl,and the like. “Halogenalkoxy” includes trifluoromethyloxy.

[0014] “Pharmaceutically acceptable,” such as pharmaceuticallyacceptable carrier, excipient, etc., means pharmacologically acceptableand substantially non-toxic to the subject to which the particularcompound is administered.

[0015] “Pharmaceutically acceptable salts” of a compound means saltsthat are pharmaceutically acceptable, which are generally safe,non-toxic, and neither biologically nor otherwise undesirable, and thatpossess the desired pharmacological activity of the parent compound.These salts are derived from an inorganic or organic acid or base. Ifpossible, Active Compounds may be converted into pharmaceuticallyacceptable salts. It should be understood that pharmaceuticallyacceptable salts are included in the present invention.

[0016] It should be understood that all references to pharmaceuticallyacceptable salts include solvent addition forms (solvates) or crystalforms (polymorphs) of the same acid addition salt.

[0017] “Therapeutically effective amount” means an amount that iseffective to prevent, alleviate or ameliorate symptoms of disease orprolong the survival of the subject being treated.

[0018] The invention relates to racemic or enantiomerically pure4-pyrrolidino derivatives, processes for their preparation,pharmaceutical compositions comprising said derivatives, and their usein the prevention and treatment of illness.

[0019] More particularly, the present invention relates to compounds ofthe formula I

[0020] wherein

[0021] Q is ═N— or ═C(R²⁴)—;

[0022] X—Y is —CH₂—CH₂—, —CH═CH— or —CH₂—O—;

[0023] R¹, R^(1.1) and R^(1.2) independently from each other areselected from the group consisting of hydrogen, halogen, (C₁-C₆)-alkyl,halogen-(C₁-C₆)-alkyl, cyano, (C₁-C₆)-alkoxy or halogen-(C₁-C₆)-alkoxy;

[0024] R²¹, R²² and R²³ independently from each other are selected fromthe group consisting of hydrogen and halogen;

[0025] R²⁴ is hydrogen, halogen or methyl;

[0026] R³ is —C(O)N(H)CH₃ or —CH₂CN; and

[0027] R⁴ is hydrogen;

[0028] as well as individual isomers, racemic or non-racemic mixturesthereof.

[0029] Even more particularly, the present invention relates tocompounds of the formula I*

[0030] wherein

[0031] R¹ is halogen, halogen-(C₁-C₆)-alkyl, cyano, (C₁-C₆)-alkoxy orhalogen-(C₁-C₆)-alkoxy;

[0032] R²¹, R²², R²¹ and R²⁴ independently from each other are selectedfrom the group consisting of hydrogen and halogen;

[0033] R³ is —CONHR⁵, —CH₂CN or —CN;

[0034] R⁴ is hydrogen;

[0035] R⁵ is methyl; and

[0036] n is 0, 1, 2 or 3;

[0037] as well as individual isomers, racemic or non-racemic mixturesthereof.

[0038] A more preferred group of compounds of formula I* are thosewherein R³ is —CO—NHR⁵ and R⁵ is methyl.

[0039] Examples of such compounds are the following:

[0040](RS)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,

[0041](R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,

[0042](RS)-[1-[4-(3,4-difluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,

[0043](RS)-[1-[4-(2,6-difluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,

[0044](RS)-1-[4-(3-chloro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,

[0045](RS)-1-[3-fluoro-4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,

[0046](RS)-1-[2-fluoro-4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,

[0047] (RS)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acidmethylamide, and

[0048] (R)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acidmethylamide.

[0049] A further preferred group of compounds of formula I* are those,wherein R³ is —CH₂CN and R⁴ is hydrogen.(RS)-1-[4-(3,4-difluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetonitrileis an example for such a compound.

[0050] Compounds of formula I* may be substituted by n R¹ selected fromthe group consisting of halogen, halogen-(C₁-C₆)-alkyl, cyano,(C₁-C₆)-alkoxy or halogen-(C₁-C₆)-alkoxy, wherein n denotes an integerselected from 0, 1, 2 and 3. Preferably n is 1 or 2.

[0051] Preferred compounds of formula I* are those, wherein R¹ ishalogen or halogen-(C₁-C₆)-alkyl. Especially preferred are thosecompounds of formula I*, wherein R¹ is fluorine, chlorine ortrifluoromethyl. Where the compounds are substituted by two or three R¹,each R¹ can be the same or different.

[0052] In one embodiment the invention provides compounds of formula Iwherein Q is ═C(R²⁴)—, wherein R²⁴ is hydrogen, halogen or methyl. Inanother embodiment the invention provides compounds of formula I whereinQ is ═CH—, ═CF— or ═C(CH₃)—. In still another embodiment the inventionprovides compounds of formula I wherein Q is ═N—.

[0053] In one embodiment the invention provides compounds of formula Iwherein —X—Y— is —CH₂—O—. In another embodiment the invention providescompounds of formula I wherein —X—Y— is —CH₂—CH₂— or —CH═CH—.

[0054] In one embodiment the invention provides compounds of formula Iwherein R¹, R^(1.1) and R^(1.2) independently from each other areselected from the group consisting of hydrogen, halogen, methyl,halogenmethyl, cyano, methoxy or halogen-methoxy. In another embodimentthe present invention provides compounds of formula I wherein R¹,R^(1.1) and R^(1.2) are halogen, e.g. fluoro, e.g. 2,4,6-trifluoro,2,4,5-trifluoro, 2,3,6-trifluoro, 2,3,4-trifluoro or 3,4,5-trifluoro. Instill another embodiment the present invention provides compounds offormula I wherein R^(1.2) is hydrogen and R¹ and R^(1.1) independentlyfrom each other are selected from the group consisting of hydrogen,halogen, (C₁-C₆)-alkyl, halogen-(C₁-C₆)-alkyl, cyano, (C₁-C₆)-alkoxy orhalogen-(C₁-C₆)-alkoxy. In still another embodiment the presentinvention provides compounds of formula I wherein R^(1.2) is hydrogenand R¹ and R^(1.1) independently from each other are selected from thegroup consisting of halogen and (C₁-C₆)-alkyl. In still anotherembodiment the present invention provides compounds of formula I whereinR^(1.2) is hydrogen, R^(1.1) is halogen and R¹ is halogen or(C₁-C₆)-alkyl. In still another embodiment the present inventionprovides compounds of formula I wherein R^(1.1) and R^(1.2) are hydrogenand R¹ is halogen, (C₁-C₆)-alkyl, halogen-(C₁-C₆)-alkyl, cyano,(C₁-C₆)-alkoxy or halogen-(C₁-C₆)-alkoxy. In still another embodimentthe present invention provides compounds of formula I wherein R^(1.1)and R^(1.2) are hydrogen and R¹ is halogen, methyl, halogenmethyl,cyano, methoxy or halogen-methoxy. In still another embodiment thepresent invention provides compounds of formula I wherein R^(1.1) andR^(1.2) are hydrogen and R¹ is fluoro, e.g. 3-fluoro or 4-fluoro,chloro, e.g. 3-chloro, halogenmethyl, e.g. 3-trifluoromethyl, cyano,methoxy, e.g. 2-methoxy, 3-methoxy or 4-methoxy, or halogen-methoxy,e.g. 3-trifluoromethoxy. In another embodiment the present inventionprovides compounds of formula I wherein R¹, R^(1.1) and R^(1.2) arehydrogen.

[0055] In one embodiment the present invention provides compounds offormula I wherein R²¹, R²² and R²³ are hydrogen. In another embodimentthe present invention provides compounds of formula I wherein R²¹ andR²³ are hydrogen and R²² is fluoro.

[0056] In one embodiment the present invention provides compounds offormula I wherein R³ is —C(O)N(H)CH₃. In another embodiment the presentinvention provides compounds of formula I wherein R³ is —CH₂CN.

[0057] In one aspect the present invention provides compounds of formulaI wherein the compounds have (R)-configuration.

[0058] In one embodiment the present invention provides compounds offormula I wherein Q is ═C(R²⁴)—, wherein R²⁴ is hydrogen, halogen ormethyl; —X—Y— is —CH₂—O—; R¹, R^(1.1) and R^(1.2) independently fromeach other are selected from the group consisting of hydrogen, halogen,methyl, halogenmethyl, cyano, methoxy or halogen-methoxy; R²¹, R²² andR²³ are hydrogen; and R³ is —C(O)N(H)CH₃.

[0059] In another embodiment the present invention provides compounds offormula I wherein Q is ═CH—; —X—Y— is —CH₂—O—; R²¹, R²² and R²³ arehydrogen; and R³ is —C(O)N(H)CH₃. In yet another embodiment, theinvention provides compounds of formula I wherein Q is ═CH—; —X—Y— is—CH₂—O—; R¹, R^(1.1) and R^(1.2) independently from each other areselected from the group consisting of hydrogen, halogen, methyl,halogenmethyl, cyano, methoxy or halogen-methoxy; R²¹, R²² and R²³ arehydrogen; and R³ is —C(O)N(H)CH₃. In still another embodiment thepresent invention provides compounds of formula I wherein Q is ═CH—;—X—Y— is —CH₂—O—; R^(1.1) and R^(1.2) are hydrogen and R¹ is fluoro,chloro, halogenmethyl, cyano, methoxy or halogen-methoxy; R²¹, R²² andR²³ are hydrogen; and R³ is —C(O)N(H)CH₃.

[0060] Examples of compounds of formula I include compounds selectedfrom

[0061](RS)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,

[0062](RS)-[1-[4-(4-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,

[0063](RS)-1-[4-(3-chloro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,

[0064](RS)-[1-[4-(3,4-difluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,

[0065](RS)-[1-[4-(2,6-difluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,

[0066](RS)-5-oxo-1-[4-(2,4,6-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methyl amide,

[0067](RS)-5-oxo-1-[4-(2,4,5-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methylamide,

[0068](RS)-5-oxo-1-[4-(2,3,6-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methylamide,

[0069](RS)-5-oxo-1-[4-(2,3,4-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methyl amide,

[0070](RS)-5-oxo-1-[4-(3,4,5-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methyl amide,

[0071](RS)-1-[4-(5-fluoro-2-methyl-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,

[0072](RS)-1-[4-(3-methoxy-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,

[0073](RS)-1-[4-(2-methoxy-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,

[0074](RS)-5-oxo-1-[4-(3-trifluoromethoxy-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methylamide,

[0075](RS)-5-oxo-1-[4-(3-trifluoromethyl-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methylamide,

[0076](RS)-1-[4-(3-cyano-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,

[0077](RS)-1-[4-(3-fluoro-benzyloxy)-3-methyl-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,

[0078](RS)-1-[4-(4-fluoro-benzyloxy)-3-methyl-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,

[0079](RS)-1-[4-(3-chloro-benzyloxy)-3-methyl-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,

[0080](RS)-1-[3-fluoro-4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,

[0081](RS)-1-[2-fluoro-4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,

[0082](RS)-1-[2,5-difluoro-4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,

[0083] (RS)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acidmethylamide,

[0084](R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,

[0085](S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,

[0086] (R)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acidmethylamide,

[0087] (S)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acidmethylamide,

[0088](R)-1-[4-(4-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,

[0089](R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,

[0090](R)-1-[4-(3-chloro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,

[0091](R)-1-[4-(2,6-difluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methyl amide,

[0092](R)-5-oxo-1-[4-(2,4,6-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methylamide,

[0093](RS)-1-[4-(3,4-difluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetonitrile,

[0094](RS)-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetonitrile,

[0095] (RS)-[1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidin-3-yl]-acetonitrile,

[0096](RS)-(E)-1-{4-[2-(3-fluoro-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methylamide,

[0097](RS)-(E)-1-{4-[2-(4-methoxy-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methylamide,

[0098](RS)-(E)-1-{4-[2-(3-methoxy-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methylamide,

[0099](RS)-(E)-1-{4-[2-(4-fluoro-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methyl amide,

[0100](RS)-1-{4-[2-(3-chloro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methylamide,

[0101](RS)-1-{4-[2-(4-chloro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methylamide,

[0102](RS)-1-{4-[2-(3-fluoro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methyl amide,

[0103](RS)-1-{4-[2-(4-fluoro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methylamide,

[0104](RS)-1-{4-[2-(3-methoxy-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methylamide,

[0105](RS)-1-[6-(4-fluoro-benzyloxy)-pyridin-3-yl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide, and

[0106](RS)-1-[4-(2-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide.

[0107] In another embodiment the present invention provides a processfor the preparation of compounds of formula I comprising reacting acompound of formula II

[0108] wherein R¹, R^(1.1), R^(1.2), R²¹, R²², R²³, R⁴, —X—Y— and Q havethe above meanings and R* is hydrogen or (C₁-C₆)-alkyl

[0109] (a) with an amine of formula H₂N—CH₃, obtaining compounds offormula I wherein R³ is —C(O)N(H)CH₃; or

[0110] (b) reducing a compound of formula II to a compound of formulaIII

[0111] wherein R¹, R^(1.1), R^(1.2), R²¹, R²², R²³, R⁴, —X—Y— and Q havethe above meanings and reacting this compound with a cyanide salt,obtaining compounds of formula I wherein R³ is CH₂CN.

[0112] The compounds of general formula I* can be manufactured byreacting a compound of formula II*

[0113] wherein R¹, R²¹, R²², R²³, R²⁴ and n have the above meanings

[0114] with an amine of formula H₂N—R⁵, wherein R⁵ has the abovemeaning, to obtain a compound of formula Ia*

[0115] or, alternatively, reducing a compound of formula II* to thecorresponding alcohol of formula III*

[0116] and reacting this compound with a cyanide salt to obtain acompound of formula Ib*

[0117] or, alternatively,

[0118] reacting a compound of formula IV*

[0119] wherein X is halogen, with a cyanide salt, to obtain a compoundof formula Ic*

[0120] All starting materials employed in the processes described hereinare either commercially available or can be prepared by conventionalmeans.

[0121] In accordance with the present invention, scheme 1 shows the mainroutes to compounds of the formula I wherein R³ is —C(O)N(H)CH₃, i.e.compounds of formula I**.

[0122] The reaction of the intermediates IV and IVa with itaconic acid Vis preferentially done neat at temperatures between 80° C. and 200° C.Compounds of formula IIa and IVa are then transformed to esters offormula IIb and VIa by methods known per se.

[0123] Compounds of formula VIa can then be alkylated byWilliamson-ether synthesis using optionally substituted benzylichalides, tosylates, mesylates or triflates. Bases used can be, e.g.,alcoholates or carbonates, like e.g. sodium, potassium or cesiumcarbonate. Examples for solvents are lower alcohols, acetonitrile orlower ketones. The temperature may be, e.g. in the range of from 20° C.to reflux temperature. Another approach is the Mitsunobu-coupling ofoptionally substituted benzylic alcohols with phenol VIa. The reactionmay be done as usual in inert solvents, e.g., diethyl ether ortetrahydrofurane, using dialkyl-azo-dicarboxylates in the presence ofphosphines (e.g. tributyl- or triphenyl-phosphine). The hydrolysis ofcompounds of formula VIa can be performed by methods known per se likehydrolysis under acidic conditions, e.g. with hydrochloric acid, orbasic conditions, e.g. lithium, sodium- or potassium hydroxide inmixtures of alcohols and water as the solvent.

[0124] In compounds of formula I** or IIb where —X—Y— has the meaning of—CH₂—O—, the optionally substituted benzyl residue can function as atransient group which can be cleaved by hydrogenolysis. The resultingphenols VIa and VIb can then be re-alkylated by a different benzyl groupunder the aforementioned conditions. As known to those skilled in theart, this process is only possible on condition that the othersubstituents are stable under the aforementioned reaction conditions forthe hydrogenolysis and alkylation reaction, eg. formyl or acetyl for R⁶,tert-butoxycarbonyl (BOC) for PG.

[0125] Amides of formula I** or VIb can be obtained by aminolysis ofesters of formula IIb or VIa with amines of formula R⁵—NH₂ at atemperature in the range of from room temperature (RT) and 120° C., e.g.in sealed tubes using solvents inert under these conditions, like e.g.dimethoxyethane, dioxane, or methanol. Alternatively, acids of formulaIIa may be transformed into compounds of formula I** using standardprocedures. They can be activated via, e.g., acid chloride or mixedanhydride. Especially for the preparation of enantiopure derivatives,condensation reagents like carbodiimides, e.g.dicyclohexyl-carbodiimide, or benzotriazol derivatives, e.g.0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate(HBTU) may be applied.

[0126] Another method to prepare compounds of formula I involvescross-coupling reactions of arylstannanes [Lam et al., Tetrahedron Lett.43:3091 (2002)], arylboronates [Lam et al., Synlett 5:674 (2000); Chanet al., Tetrahedron Lett. 39:2933 (1998)] or aryl halides [Buchwald etal., J. Amer. Chem. Soc. 118:7215 (1996)] with the correspondingpyrrolidones (scheme 2).

[0127] wherein LG is a leaving group, e.g. halogen, e.g. Cl, Br or I, orSnR₃ or B(OH)₂, and R³′ is —CONHR⁵ or —CH₂CN or alkoxycarbonyl.

[0128] In accordance with the present invention, one method to preparethe intermediates of general formula IV, wherein —X—Y— is —CH₂—O—, i.e.a compound of formula IVb, is shown in scheme 3: The intermediates offormula XII are accessible through nucleophilic substitution of aromaticnitro compounds of formula XI containing p-substituted leaving groupswith benzylic alcohols of formula X. Leaving groups in para-position canbe, e.g., halogens (F, Cl, Br, I), tosylates, mesylates or triflates.These substitution reactions can be conducted neat or in inert solvents,e.g., toluene or xylene. The reaction temperature may be in the range offrom 50° C. to 150° C.

[0129] Alternatively, compounds of formula XII can be prepared byWilliamson-ether synthesis, starting from p-nitrophenols of formula XIVand benzylic halides, tosylates, mesylates or triflates of formula XIII.Bases used can be, e.g., alcoholates or carbonates (sodium, potassium orcesium carbonate). Examples for solvents are lower alcohols,acetonitrile or lower ketones. The temperature may be in the range offrom 20° C. to reflux temperature. Another approach is theMitsunobu-coupling of benzylic alcohols with p-nitrophenols of formulaXIV. The reaction is done as usual in inert solvents like for examplediethyl ether or tetrahydrofurane, using dialkyl azo-dicarboxylates inthe presence of phosphines like e.g. tributyl- or triphenyl-phosphine.

[0130] The key intermediates of formula XII are reduced to the aminocompounds of formula IVb using catalytic hydrogenation, like e.g. usingplatinum on charcoal as the catalyst in lower alcohols, ethyl acetate ortetrahydrofurane. An alternative is the reduction of the nitro-group bymetals like iron, tin, or zinc in acidic media, like dilutedhydrochloric acid or acetic acid. Metals can also be replaced by metalsalts like e.g. tin-(II)-chloride.

[0131] wherein LG is a leaving group, e.g. halogen, OTf, etc., and Y isa leaving group, e.g. halogen, OTf, etc. or OH (for Mitsunobu-coupling).

[0132] In accordance with the present invention, one method to preparethe intermediates of formula IVd (wherein —X—Y— is —CH═CH—) and IVc(wherein —X—Y— is —CH₂—CH₂—) is shown in scheme 4: The intermediates offormula XVII are accessible by olefination reaction of optionallysubstituted aromatic aldehydes of formula XV with dialkyl(4-nitrobenzyl)-phosphonates of formula XVI in the presence of a base,like e.g. sodium hydride, yielding the corresponding nitro-olefins offormula XVII.

[0133] The key intermediates of formula XVII can be reduced selectivelyto the amino-olefins of formula IVd using catalytic hydrogenation likee.g. using platinum on charcoal as the catalyst in lower alcohols, ethylacetate or tetrahydrofurane as the solvent, or, by metals or metalsalts, like e.g. tin-(II)-chloride. The amino derivatives of formula IVccan be obtained directly from the nitro derivatives of formula XVII orfrom the amino-olefins of formula IVd by hydrogenation using palladiumon charcoal as the catalyst in lower alcohols, ethyl acetate ortetrahydrofurane as the solvent.

[0134] Alternatively, compounds of formula II can be reduced to theintermediate compound of formula III. This may be done by firstconverting the acids of formula II into their esters (alcohol/acidcatalysis) followed by reduction with reagents like sodium borohydridein solvents like tetrahydrofurane at a temperature in the range of from20° C. to 65° C. Activation of the alcohol of formula III via mesylateor triflate and reaction with sodium or potassium cyanide at atemperature in the range of from 40° C. to 80° C. leads to the desiredcompounds of formula I wherein R³ is CH₂CN, i.e. nitrites of formula Ib.

[0135] Compounds of general formula I can also exist in optical pureform. Separation into antipodes can be affected according methods knownper se, either at an early stage of the synthesis, e.g. starting withcompounds of formula Ia by salt formation with an optically active aminesuch as, for example, ((+))- or (−)-1-phenylethylamine or ((+))- or(−)-1-naphthylethylamine and separation of the diastereomeric salts byfractional crystallisation, or by derivatisation with a chiral auxiliarysubstance such as, for example, ((+))- or (−)-2-butanol, ((+))- or(−)-1-phenylethanol, or ((+))- or (−)-menthol and separation of thediastereomeric products by chromatography and/or crystallisation andsubsequent cleavage of the bond to the chiral auxiliary substance; or,on the very last stage, by separation of the enantiomers of formula I bychromatography on a chiral phase.

[0136] Furthermore, compounds of formula I can also be obtained fromenantiopure intermediates obtained by biotransformation, e.g. byhydrolysis of esters of formula VIa by enzymes, such as e.g.cholesterase from Candida cylindracea. In order to determine theabsolute configuration of the pyrrolidinone derivative obtained, thepure diastereomeric salts or derivatives can be analysed by conventionalspectroscopic methods, e.g. with X-ray spectroscopy on single crystals.

[0137] The Active Compounds are, as already mentioned above, monoamineoxidase B inhibitors and can be used for the treatment or prevention ofdiseases in which MAO-B inhibitors might be beneficial. These includeacute and chronic neurological disorders, cognitive disorders and memorydeficits. Treatable neurological disorders are for instance traumatic orchronic degenerative processes of the nervous system, such asAlzheimer's disease, other types of dementia, minimal cognitiveimpairment or Parkinson's disease.

[0138] Other indications include psychiatric diseases such asdepression, anxiety, panic attack, social phobia, schizophrenia, eatingand metabolic disorders such as obesity, as well as the prevention andtreatment of withdrawal syndromes induced by abuse of alcohol, nicotineand other addictive drugs. Other treatable indications may be peripheralneuropathy caused by cancer chemotherapy (WO 97/33,572), rewarddeficiency syndrome (WO 01/34,172), or the treatment of multiplesclerosis (WO 96/40,095), and other neuroinflammatory diseases.

[0139] The Active Compounds are especially useful for the treatment andprevention of Alzheimer's disease and senile dementia.

[0140] The pharmacological activity of the compounds was tested usingthe following method:

[0141] The cDNAs encoding human MAO-A and MAO-B were transientlytransfected into EBNA cells using the procedure described by Schlaegerand Christensen [Cytotechnology 15: 1-13 (1998)]. After transfection,cells were homogenised by means of a Polytron homogenizer in 20 mM TrisHCl buffer, pH 8.0, containing 0.5 mM EGTA and 0.5 mMphenylmethanesulfonyl fluoride. Cell membranes were obtained bycentrifugation at 45,000× g and, after two rinsing steps with 20 mM TrisHCl buffer, pH 8.0, containing 0.5 mM EGTA, membranes were eventuallyre-suspended in the above buffer and aliquots stored at −80° C. untiluse.

[0142] MAO-A and MAO-B enzymatic activity was assayed in 96-well-platesusing a spectrophotometric assay adapted from the method described byZhou and Panchuk-Voloshina [Analytical Biochemistry 253:169-174 (1997)].Briefly, membrane aliquots were incubated in 0.1 M potassium phosphatebuffer, pH 7.4, for 30 min at 37° C. containing different concentrationsof the compounds. After this period, the enzymatic reaction was startedby the addition of the MAO substrate tyramine together with 1 U/mlhorse-radish peroxidase (Roche Biochemicals) and 80 μMN-acetyl-3,7-dihydroxyphenoxazine (Amplex Red, Molecular Probes). Thesamples were further incubated for 30 min at 37° C. in a final volume of200 μl and absorbance was then determined at a wavelength of 570 nmusing a SpectraMax plate reader (Molecular Devices). Background(non-specific) absorbance was determined in the presence of 10 μMclorgyline for MAO-A or 10 μM L-deprenyl for MAO-B. IC₅₀ values weredetermined from inhibition curves obtained using nine inhibitorconcentrations in duplicate, by fitting data to a four parameterlogistic equation using a computer program.

[0143] The compounds of the present invention are specific MAO-Binhibitors. The IC₅₀ values of preferred Active Compounds as measured inthe assay described above are in the range of 1 μM or less, typically0.1 μM or less, and ideally 0.02 μM or less.

[0144] The present invention also provides pharmaceutical compositionscontaining Active Compounds, or pharmaceutically acceptable saltsthereof, and a pharmaceutically acceptable carrier. Active Compoundsinclude individual isomers and racemic and non-racemic mixtures thereof.Such pharmaceutical compositions can be in the form of tablets, coatedtablets, dragees, hard and soft gelatine capsules, solutions, emulsionsor suspensions. The pharmaceutical compositions also can be in the formof suppositories or injectable solutions.

[0145] The pharmaceutical compositions of the invention, in addition toone or more Active Compounds, contain a pharmaceutically acceptablecarrier. Suitable pharmaceutically acceptable carriers includepharmaceutically inert, inorganic or organic carriers. Lactose, cornstarch or derivatives thereof, talc, stearic acid or its salts and thelike can be used, for example, as such carriers for tablets, coatedtablets, dragees and hard gelatine capsules. Suitable carriers for softgelatine capsules are, for example, vegetable oils, waxes, fats,semi-solid and liquid polyols and the like; depending on the nature ofthe active substance no carriers are, however, usually required in thecase of soft gelatine capsules. Suitable carriers for the production ofsolutions and syrups are, for example, water, polyols, sucrose, invertsugar, glucose and the like. Adjuvants, such as alcohols, polyols,glycerol, vegetable oils and the like, can be used for aqueous injectionsolutions of water-soluble salts of Active Compounds, but as a rule arenot necessary. Suitable carriers for suppositories are, for example,natural or hardened oils, waxes, fats, semi-liquid or liquid polyols andthe like.

[0146] In addition, the pharmaceutical preparations can containpreservatives, solubilizers, stabilizers, wetting agents, emulsifiers,sweeteners, colorants, flavorants, salts for varying the osmoticpressure, buffers, masking agents or antioxidants. They may also containother therapeutically valuable substances.

[0147] Compounds of the invention are selective MAO-B inhibitors.Therefore, the present invention also provides methods of treating orpreventing diseases that are mediated by monoamine oxidase B. Suchmethods include administering a therapeutically effective amount of anActive Compound, for example, a compound of formula I or I*, or apharmaceutically acceptable salt thereof, to an individual in need ofsuch treatment. In one embodiment, the invention provides a method forthe treatment or prevention of Alzheimer's disease by administering toan individual a therapeutically effective amount of an Active Compound,e.g., a compound of formula I or I*. In another embodiment, the presentinvention provides a method for the treatment or prevention of seniledementia by administering to an individual a therapeutically effectiveamount of an Active Compound, e.g., a compound of formula I or I*.

[0148] The compounds and compositions of the present invention can beadministered in a conventional manner, for example, orally, rectally, orparenterally. The pharmaceutical compositions of the invention can beadministered orally, for example, in the form of tablets, coatedtablets, dragees, hard and soft gelatine capsules, solutions, emulsions,or suspensions. The pharmaceutical compositions also can be administeredrectally, for example, in the form of suppositories, or parenterally,for example, in the form of injection solutions.

[0149] The dosage at which the Active Compound is administered can varywithin wide limits and will, of course, be fitted to the individualrequirements in each particular case. In general, the effective dosagefor oral or parenteral administration is between 0.01-20 mg/kg/day, witha dosage of 0.1-10 mg/kg/day being preferred for all of the indicationsdescribed. The daily dosage for an adult human being weighing 70 kgaccordingly lies between 0.7-1400 mg per day, preferably between 7 and700 mg per day.

[0150] The following examples are provided for illustration of theinvention. They should not be considered as limiting the scope of theinvention, but merely as being representative thereof. Unless otherwiseindicated, the following examples have been performed, regardless of thetense in which they are written. The abbreviation “RT” means “roomtemperature.”

EXAMPLE 1(RS)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0151] a) (RS)-1-(4-Benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylicacid

[0152] 18.8 g (94.4 mmol) 4-benzyloxyaniline are mixed with 12.28 g(94.4 mmol) itaconic acid. The mixture is heated to 130° C. After 20 minthe melted material solidifies. The resulting solid is triturated withethyl acetate to yield 28.26 g (96%) of a greyish solid. MS: m/e=311(M⁽⁺⁾).

[0153] b) (RS)-1-(4-Benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylicacid methyl ester

[0154] 7.46 g (24 mmol)(RS)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid isdissolved in a mixture of 40 ml dichloromethane and 7.5 ml methanol.0.13 ml concentrated sulfuric acid is added and the reaction mixturehold under reflux over night. The solvent is evaporated and the residuetriturated with diethyl ether to yield 7.26 g (93%) of a colorless solid(used in the next step without further purification).

[0155] c) (RS)-1-(4-Hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acidmethyl ester

[0156] 7.26 g (22.3 mmol)(RS)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methylester is dissolved in 200 ml tetrahydrofuran. After addition of 726 mgpalladium 10% on charcoal hydrogenation is performed at RT and normalpressure. After 3 hours, the catalyst is filtered off and the solventevaporated to yield 6.04 g of crude product (used in the next stepwithout further purification).

[0157] d)(RS)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methyl ester

[0158] 6.04 g (RS)-1-(4-hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylicacid methyl ester, 7.10 g (51.4 mmol) potassium carbonate and 5.34 g3-fluorobenzyl bromide are suspended in 250 ml ethyl methyl ketone. Thereaction mixture is heated at 90° C. for 5 hours, cooled and poured intowater. Extraction with ethyl acetate gives a crude material which issubjected to chromatography (silica gel, n-hexane/ethyl acetate 1:1).This gives 2.10 g (24%) of a colorless solid. MS: m/e=344.3 (M(+)H)⁽⁺⁾.

[0159] e)(RS)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methyl amide

[0160] 300 mg (0.87 mmol)(RS)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methyl ester is dissolved in a mixture of 1 mlN,N-dimethylformamide and 0.18 ml of a 33% solution of methylamine inethanol. The reaction vessel is tightly stopped and hold at 120° C. for48 hours. Water is added and the product extracted with ethyl acetate.Drying and evaporation yields 92 mg (31%) of a slightly yellowishproduct. MS: m/e=343.3 (M(+)H)⁽⁺⁾.

EXAMPLE 2(RS)-[1-[4-(4-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0161] a) (RS)-1-(4-Hydroxyoxy-phenyl)-5-oxo-pyrrolidine-3-carboxylicacid

[0162] In a metallic pan, 257.0 g (2.355 mol) of 4-aminophenol and301.75 g (2.32 mol) of itaconic acid are mixed in solid form. Understirring with a metal spatula, the mixture was carefully heated on aheating plate. The temperature was measured by a thermometer. At 60° C.,the powder started to become viscous, at 110-120° C. it became liquidand the color turned to dark brown while the rest of solid material wasalso dissolved. The exothermic reaction started under boiling and, whilethe temperature raised to 150° C., the reaction mass turned to a beigesolid. The sandy product was left to cool down to RT within 1-2 hours.The crude (RS)-1-(4-hydroxyoxy-phenyl)-5-oxo-pyrrolidine-3-carboxylicacid was engaged in the next step without further purification orcharacterisation.

[0163] b) (RS)-1-(4-Hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acidmethyl ester

[0164] In a 10 1 4-necked flask equipped with a reflux condenser, athermometer, and a mechanical stirrer, the crude(RS)-1-(4-hydroxyoxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid isdissolved in a mixture of 5000 ml of methanol, 24 ml of concentratedsulfuric acid and 400 ml of 2,2-dimethoxypropane and stirred underreflux during 2 h. For the working-up, the reaction solution is reducedto half of its volume by distillation, then transferred into a 20 1vessel. Under stirring at 40° C., a mixture of 2500 ml of water/ice(1:1) is added. Crystallisation started immediately, and, thereupon, thefine white crystals are collected on a filter funnel. They are washedwith total 2000 ml of cold water until the filtrate, at the beginningbrownish-rose, becomes colorless and neutral. The well pressed andpre-dried product from the filter funnel is dried under reduced pressureto yield 980 g (84% of theory, 2 steps) of the(RS)-1-(4-hydroxyoxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methylester as a white solid; MS: m/e=234 (M(+)H)⁽⁺⁾.

[0165] c)(RS)-1-[4-(4-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methyl ester

[0166] In an analogous manner to that described in Example 1d), thealkylation of the(RS)-1-(4-hydroxyoxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methylester with 4-fluorobenzylbromide in presence of potassium carbonateyields the(RS)-1-[4-(4-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methyl ester as a light yellow powder; MS: m/e=344 (M(+)H)⁽⁺⁾.

[0167] d)(RS)-1-[4-(4-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0168] In an analogous manner to that described in Example 1e), theaminolysis of the

[0169](RS)-1-[4-(4-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methyl ester with methylamine in a sealed tube at 80° C. in ethanolduring 18 h yields the

[0170](RS)-1-[4-(4-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methyl amide as a white powder; MS: m/e=343 (M(+)H)⁽⁺⁾.

[0171] The compounds of Examples 3 to 16 are obtained in an analogousmanner to that described in Example 1d) and e), starting from(RS)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methylester, prepared following Example 1c) or Example 2b), by alkylation ofthe phenol and subsequent aminolysis of the ester:

EXAMPLE 3(RS)-1-[4-(3-Chloro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0172] In an analogous manner to that described in Example 1d) and e),starting from (RS)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylicacid methyl ester [Example 1c)] the title compound is prepared byalkylation with 3-chlorobenzyl chloride to obtain the(RS)-1-[4-(3-chloro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methyl ester as a colorless solid and, thereupon, treatment withmethylamine in ethanol at 80° C. during 18 h to yield the(RS)-1-[4-(3-chloro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide. Yield: 73% of a colorless solid. MS: m/e=359(M(+)H)⁽⁺⁾.

EXAMPLE 4(RS)-[1-[4-(3,4-Difluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0173] In an analogous manner to that described in Example 1d) and e),starting from (RS)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylicacid methyl ester [Example 1c)] the title compound is prepared byalkylation with 3,4-difluorobenzyl bromide to obtain the(RS)-1-[4-(3,4-difluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methyl ester as a colorless solid [85% of theory; MS: m/e=362.2(M⁽⁺⁾(+)H)] and, thereupon, treatment with methylamine to yield the(RS)-[1-[4-(3,4-difluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide.

[0174] Yield: 7% of a colorless solid. MS: m/e=361 (M(+)H)⁽⁺⁾.

EXAMPLE 5(RS)-[1-[4-(2,6-Difluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0175] In an analogous manner to that described in Example 1d) and e),starting from (RS)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylicacid methyl ester [Example 1c)] the title compound is prepared byalkylation with 2,6-difluorobenzyl bromide to obtain the(RS)-1-[4-(2,6-difluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methyl ester as a yellowish oil and, thereupon, treatment withmethylamine in ethanol at 80° C. during 18 h to yield the(RS)-[1-[4-(2,6-difluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide. Yield: 33% ofa colorless solid. MS: m/e=361 (M(+)H)⁽⁺⁾.

EXAMPLE 6(RS)-5-Oxo-1-14-(2,4,6-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methylamide

[0176] The title compound is prepared by alkylation of the(RS)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methylester with 2,4,6-trifluorobenzyl bromide giving the(RS)-5-oxo-1-[4-(2,4,6-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methyl ester which, thereupon, by treatment with methylamine yieldsthe(RS)-5-oxo-1-[4-(2,4,6-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methylamide. Yield: 97% of theory as a white solid. MS: m/e=379(M(+)H)⁽⁺⁾.

EXAMPLE 7(RS)-5-Oxo-1-[4-(2,4,5-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methylamide

[0177] The title compound is prepared by alkylation of the(RS)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methylester with 2,4,5-trifluorobenzyl bromide giving the(RS)-5-oxo-1-[4-(2,4,5-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methyl ester as a white solid (83% of theory) which, thereupon, bytreatment with methylamine yields the(RS)-5-oxo-1-[4-(2,4,5-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methylamide as a light yellow solid; MS:

[0178] m/e=379 (M(+)H)⁽⁺⁾.

EXAMPLE 8(RS)-5-Oxo-1-[4-(2,3,6-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methylamide

[0179] The title compound is prepared by alkylation of the(RS)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methylester with 2,3,6-trifluorobenzyl bromide giving the(RS)-5-oxo-1-[4-(2,3,6-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methyl ester as a light yellow solid [73% of theory, MS: m/e=379(M(+)H)⁽⁺⁾], which, thereupon, by treatment with methylamine yields the(RS)-5-oxo-1-[4-(2,3,6-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methylamide. Yield: 64% of theory as a white solid. MS: m/e=379(M(+)H)⁽⁺⁾.

EXAMPLE 9(RS)-5-Oxo-1-[4-(2,3,4-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methylamide

[0180] The title compound is prepared by alkylation of the(RS)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methylester with 2,3,4-trifluorobenzyl bromide giving the(RS)-5-oxo-1-[4-(2,3,4-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methyl ester as a white solid (94% of theory) which, thereupon, bytreatment with methylamine in ethanol at 50° C. yields the(RS)-5-oxo-1-[4-(2,3,4-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methylamide. Yield: 99% of theory as a white solid; MS: m/e=379(M(+)H)⁽⁺⁾.

EXAMPLE 10(RS)-5-Oxo-α-[4-(3,4,5-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methylamide

[0181] The title compound is prepared by alkylation of the(RS)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methylester with 2,4,6-trifluorobenzyl bromide giving the(RS)-5-oxo-1-[4-(3,4,5-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methyl ester as a white solid (99% of theory) which, thereupon, bytreatment with methylamine in ethanol at 50° C. yields the(RS)-5-oxo-1-[4-(3,4,5-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methylamide. Yield: 99% of theory as a white solid; MS: m/e=379(M(+)H)⁽⁺⁾.

EXAMPLE 11(RS)-1-[4-(5-Fluoro-2-methyl-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0182] The title compound is prepared by alkylation of the(RS)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methylester with 5-fluoro-2-methylbenzyl bromide giving the(RS)-1-[4-(5-fluoro-2-methyl-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methyl ester as a white solid [71% of theory, MS: m/e=358(M(+)H)⁽⁺⁾] which, thereupon, by treatment with methylamine in ethanolat 60° C. during 4 h yields the(RS)-1-[4-(5-fluoro-2-methyl-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide. Yield: 53% of theory as a colorless solid. MS: m/e=357(M(+)H)⁽⁺⁾.

EXAMPLE 12(RS)-1-[4-(3-Methoxy-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0183] In an analogous manner to that described in Example 1 d) and e),starting from (RS)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylicacid methyl ester [Example 1c)] the title compound is prepared byalkylation with 3-methoxybenzyl bromide to obtain the(RS)-1-[4-(3-methoxy-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methyl ester as a yellowish oil and, thereupon, treatment withmethylamine in ethanol at 80° C. during 18 h to yield the(RS)-1-[4-(3-methoxy-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide. Yield: 75% of a colorless solid. MS: m/e=355(M(+)H)⁽⁺⁾.

EXAMPLE 13(RS)-1-[4-(2-Methoxy-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0184] The title compound is prepared by alkylation of the(RS)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methylester with 2-methoxybenzylbromide giving the(RS)-1-[4-(2-methoxy-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methyl ester as a light yellow oil [83% of theory, MS: m/e=355(M(+)H)⁽⁺⁾ which, thereupon, by treatment with methylamine in ethanol at80° C. yields the(RS)-1-[4-(2-methoxy-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide. Yield: 47% of theory as a white solid. MS: m/e=355(M(+)H)⁽⁺⁾.

EXAMPLE 14(RS)-5-Oxo-1-[4-(3-trifluoromethoxy-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methylamide

[0185] The title compound is prepared by alkylation of the(RS)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methylester with 3-trifluoromethoxybenzyl bromide giving the(RS)-5-oxo-1-[4-(3-trifluoromethoxy-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methyl ester as a white solid [40% of theory, MS: m/e=410(M(+)H)⁽⁺⁾] which, thereupon, by treatment with methylamine in ethanolat 80° C. yields the(RS)-5-oxo-1-[4-(3-trifluoromethoxy-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methylamide. Yield: 59% of theory as a white powder. MS: m/e=409(M(+)H)⁽⁺⁾.

EXAMPLE 15(RS)-5-Oxo-1-[4-(3-trifluoromethyl-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methylamide

[0186] In an analogous manner to that described in Example 1 d) and e),starting from (RS)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylicacid methyl ester [Example 1c)] the title compound is prepared byalkylation with 3-(trifluoromethyl)benzyl chloride to obtain the(RS)-5-oxo-1-[4-(3-trifluoromethyl-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methyl ester as a yellowish solid and, thereupon, treatment withmethylamine in ethanol at 80° C. during 18 h to yield the(RS)-5-oxo-1-[4-(3-trifluoromethyl-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methylamide. Yield: 54% of a colorless solid. MS: m/e=393(M(+)H)⁽⁺⁾.

EXAMPLE 16(RS)-1-[4-(3-Cyano-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0187] The title compound is prepared by alkylation of the(RS)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methylester with 3-cyanobenzyl bromide giving the(RS)-1-[4-(3-cyano-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylester as a light yellow solid [69% of theory, MS: m/e=351(M(+)H)⁽⁺⁾] which, thereupon, by treatment with methylamine in ethanolat 80° C. yields the(RS)-1-[4-(3-cyano-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide. Yield: 79% of theory as a white powder. MS: m/e=350(M(+)H)⁽⁺⁾.

EXAMPLE 17(RS)-1-[4-(3-Fluoro-benzyloxy)-3-methyl-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0188] a)(RS)-1-(4-Hydroxy-3-methyl-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid

[0189] In an analogous manner to that described in Example 2a),4-amino-o-cresol is reacted with itaconic acid at 140° C. during 10 minto yield the(RS)-1-(4-hydroxy-3-methyl-phenyl)-5-oxo-pyrrolidine-3-carboxylic acidas a light brown solid; MS: m/e=234 (M−H)⁽⁺⁾ which directly used in thenext step.

[0190] b)(RS)-1-(4-Hydroxy-3-methyl-phenyl)-5-oxo-pyrrolidine-3-carboxylic acidmethyl ester

[0191] In analogy to the esterification described in Example 2b), the(RS)-1-(4-hydroxy-3-methyl-phenyl)-5-oxo-pyrrolidine-3-carboxylic acidis reacted with methanol in presence of sulfuric acid to yield the(RS)-1-(4-hydroxy-3-methyl-phenyl)-5-oxo-pyrrolidine-3-carboxylic acidmethyl ester as a light brown solid; MS: m/e=250 (M(+)H)⁽⁺⁾.

[0192] c)(RS)-1-[(4-(3-Fluoro-benzyloxy)-3-methyl-phenyl)-5-oxo-pyrrolidine-3-carboxylicacid methyl ester

[0193] In analogy to the alkylation described in Example 1d), the(RS)-1-(4-hydroxy-3-methyl-phenyl)-5-oxo-pyrrolidine-3-carboxylic acidmethyl ester is reacted with 3-fluorobenzyl bromide in presence ofpotassium carbonate in DMF at 80° C. to yield the(RS)-1-[(4-(3-fluoro-benzyloxy)-3-methyl-phenyl)-5-oxo-pyrrolidine-3-carboxylicacid methyl ester as a light brown oil; MS: m/e=375 (M(+)NH₄)⁽⁺⁾.

[0194] d)(RS)-1-[(4-(3-Fluoro-benzyloxy)-3-methyl-phenyl)-5-oxo-pyrrolidine-3-carboxylicacid methyl amide

[0195] In analogy to the aminolysis described in Example 1e), the(RS)-1-[(4-(3-fluoro-benzyloxy)-3-methyl-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester istreated in a sealed tube with methylamine in ethanol at 60° C. for 18 hto yield the

[0196](RS)-1-[(4-(3-fluoro-benzyloxy)-3-methyl-phenyl)-5-oxo-pyrrolidine-3-carboxylicacid methyl amide as a light yellow solid; MS: m/e=357 (M(+)H)⁽⁺⁾.

EXAMPLE 18(RS)-1-[4-(4-Fluoro-benzyloxy)-3-methyl-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0197] The title compound is prepared by alkylation of the(RS)-1-(4-hydroxy-3-methyl-phenyl) -5-oxo-pyrrolidine-3-carboxylic acid[Example 17b)] with 4-fluorobenzylbromide, in analogy to Example 1d),giving the (RS)-1-[4-(4-fluoro-benzyloxy)-3-methyl-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylester as alight brown solid [26% of theory, MS: m/e=358 (M(+)H)⁽⁺⁾] which,thereupon, by treatment with methylamine in ethanol at 80° C., inanalogy to Example 1e), yields the(RS)-1-[4-(4-fluoro-benzyloxy)-3-methyl-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide. Yield: 79% of theory as an off-white solid. MS:m/e=357 (M(+)H)⁽⁺⁾.

EXAMPLE 19(RS)-1-[4-(3-Chloro-benzyloxy)-3-methyl-phenyl[-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0198] The title compound is prepared by alkylation of the(RS)-1-(4-hydroxy-3-methyl-phenyl) -5-oxo-pyrrolidine-3-carboxylic acid[Example 17b)] with 3-chlorobenzylchloride, in analogy to Example 1d),giving the (RS)-1-[4-(3-chloro-benzyloxy)-3-methyl-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylester as alight brown oil [47% of theory, MS: m/e=374 (M(+)H)⁽⁺⁾] which,thereupon, by treatment with methylamine in ethanol at 60° C., inanalogy to Example 1e), yields the(RS)-1-[4-(3-chloro-benzyloxy)-3-methyl-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide. Yield: 61% of theory as an white solid. MS: m/e=373(M(+)H)⁽⁺⁾.

EXAMPLE 20(RS)-1-[3-Fluoro-4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0199] a) 2-Fluoro-1-(3-fluoro-benzyloxy)-4-nitro-benzene

[0200] A mixture of 10.0 g (63.7 mmol) 2-fluoro-4-nitrophenol, 17.6 g(127 mmol) potassium carbonate and 13.24 g (70.0 mmol) 3-fluorobenzylbromide in 200 ml ethyl methyl ketone is hold overnight at 80° C. Thereaction mixture is diluted with water and extracted with ethyl acetate.Crystallisation from diethyl ether/n-hexane gives 12.68 g (75%) of aslightly yellow solid. MS: m/e=265.1 (M(+)).

[0201] b) 3-Fluoro-4-(3-fluoro-benzyloxy)-phenylamine

[0202] 12.68 g (47.8 mmol)2-fluoro-1-(3-fluoro-benzyloxy)-4-nitro-benzene is dissolved in 150 mlethyl acetate. 1.27 g platinum 5% on charcoal is added and the mixtureis hydrogenated at RT and normal pressure for 6 hours. The catalyst isfiltered off and the solution evaporated to yield 11.03 g (98%) of adark brown liquid. MS: m/e=235.1 (M(+)).

[0203] c)(RS)-1-[3-Fluoro-4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid

[0204] The title compound is prepared in analogy to Example 1a) from3-fluoro-4-(3-fluoro-benzyloxy)-phenylamine and itaconic acid. Yield:86% of a colorless solid. MS: m/e=346.1 (M−H).

[0205] d)(RS)-1-[3-Fluoro-4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0206] 500 mg (1.44 mmol)(RS)-1-[3-fluoro-4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid is suspended in 5 ml dichloromethane. 0.52 ml (7.2 mmol) thionylchloride is added and the reaction mixture hold at 40° C. overnight. Thesolvent is evaporated and the crude acid chloride is again dissolved in5 ml dichloromethane. 0.76 ml (7.2 mmol) of a 33% solution ofmethylamine in ethanol is added and the mixture heated to 40° C. for 6hours. Water is added and the product is extracted with ethyl acetate.Chromatography (silica gel, dichloromethane/methanol) yields 348 mg(67%) of a pink solid. MS: m/e=361.2 (M(+)H)⁽⁺⁾.

EXAMPLE 21(RS)-1-[2-Fluoro-4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0207] a) 2-Fluoro-4-(3-fluoro-benzyloxy)-1-nitro-benzene

[0208] The title compound is prepared in analogy to Example 20a) from3-fluoro-4-nitrophenol and 3-fluoro benzyl bromide. Yield: 100% of acolorless solid. MS: m/e=265.0 (M(+)).

[0209] b) 2-Fluoro-4-(3-fluoro-benzyloxy)-phenylamine

[0210] The title compound is prepared in analogy to Example 20b) byhydrogenation of 2-fluoro-4-(3-fluoro-benzyloxy)-1-nitro-benzene. Yield:98% of a dark brown liquid. MS: m/e=235.0 (M(+)).

[0211] c)(RS)-1-[2-Fluoro-4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid

[0212] The title compound is prepared in analogy to Example 20c) from2-fluoro-4-(3-fluoro-benzyloxy)-phenylamine and itaconic acid. Yield:67% of a purple solid. MS: m/e=346.1 (M(+)H)⁽⁺⁾.

[0213] d)(RS)-1-[2-Fluoro-4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0214] The title compound is prepared in analogy to Example 20d) from(RS)-1-[2-fluoro-4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid and methylamine. Yield: 39% of a brownish solid. MS: m/e=361.2(M(+)H)⁽⁺⁾.

EXAMPLE 22(RS)-1-[2,5-Difluoro-4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0215] a) 1,4-Difluoro-2-(3-fluoro-benzyloxy)-5-nitro-benzene

[0216] A mixture of 2.35 g (18.6 mmol) of 3-fluorobenzylalcohol and 0.55g (1.7 mmol) of tris[2-(2-methoxyethoxy)ethyl]amine is treatedportionwise under stirring with 1.06 g (18.6 mmol) of potassiumhydroxide. Stirring is continued for 10 min if necessary under slightheating to reach a homogenous reaction mixture. Thereafter, 3.0 g (16.9mmol) of 2,4,5-trifluoronitrobenzene are added dropwise. The reactionmixture becomes solid and is heated to 100° C. for 2 hours. For theworking-up, the mixture is cooled to RT, then 25 ml water and 25 mlethyl acetate are added and stirring continued for 30 min. The organiclayer is separated and the aqueous layer is extracted twice with ethylacetate. The combined organic layers are washed with water, then twicewith 2N hydrochloric acid and finally with water. After drying overmagnesium sulfate, the solution is evaporated under reduced pressure.During evaporation, the byproduct,1-fluoro-2,4-bis-(3-fluoro-benzyloxy)-5-nitro-benzene precipitates. Forpurification, the material obtained is chromatographed on silica gelusing a 4:1-mixture of n-hexane and ethyl acetate as the eluent. Thereare obtained 2.63 g (55% of theory) of the1,4-difluoro-2-(3-fluoro-benzyloxy)-5-nitro-benzene as an off-whitesolid. MS: m/e=283 (M)⁽⁺⁾.

[0217] b) 2,5-Difluoro-4-(3-fluoro-benzyloxy)-phenylamine

[0218] A solution of 2.63 g (9.3 mmol) of1,4-difluoro-2-(3-fluoro-benzyloxy)-5-nitro-benzene in 25 ml of ethylacetate is hydrogenated with Pt/C (5%) as the catalyst under normalpressure during 3 hours. For the working-up, the catalyst was filteredover a Dicalit layer and the solution evaporated under reduced pressure.There are obtained 2.25 g (95% of theory) of2,5-difluoro-4-(3-fluoro-benzyloxy)-phenylamine as a brown solid; MS:m/e=253 (M)⁽⁺⁾. The crude product is engaged in the next step withoutfurther purification.

[0219] c)(RS)-1-[2,5-Difluoro-4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid

[0220] In an analogous manner to that described in Example 1a),2,5-difluoro-4-(3-fluoro-benzyloxy) -phenylamine was reacted withitaconic acid to yield(RS)-1-[2,5-difluoro-4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid (34.5% of theory) as a grey solid; MS: m/e=363 (M−H)⁽⁺⁾.

[0221] d)(RS)-1-[2,5-Difluoro-4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0222] A solution of 365 mg (1.0 mmol) of(RS)-1-[2,5-difluoro-4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid is treated with 178 mg (1.1 mmol) of 1,1′-carbonyl-diimidazole, andthe mixture is heated at 50° C. for 2 hours. Thereafter, the solution iscooled to RT and 47 mg (1.5 mmol) of methylamine (33% solution inethanol) are added. After 18 hours the reaction is not complete, so thatanother 47 mg (1.5 mmol) of methylamine (33% solution in ethanol) areadded and stirring is continued for 24 hours at 50° C. For theworking-up, the reaction mixture is evaporated under reduced pressure.For purification, the material obtained is chromatographed on silica gelusing a 95:5-mixture of dichloromethane and methanol as the eluent.There are obtained, after crystallization from ether, 136 mg (36% oftheory) of the(RS)-1-[2,5-difluoro-4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide as an off-white solid. MS: m/e=379 (M(+)H)⁽⁺⁾.

EXAMPLE 23 (RS)-1-(4-Benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0223] The title compound is prepared in analogy to Example 20d) from(RS)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid andmethylamine. Yield: 73% of a slightly yellow solid. MS: m/e=325.4(M(+)H)⁽⁺⁾.

EXAMPLE 24(R)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0224] a)(RS)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid

[0225] 3.5 g (10.2 mmol) of [Rac]1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acidmethyl ester (Example 1d) are dispersed in 11.2 ml of a 1N solution ofsodium hydroxide, and tetrahydrofuran is added to such an extent that aclear solution is obtained. Thereupon, the reaction mixture is heated to50° C. during 1 h. For the working-up, the cooled solution is treatedwith 11.2 ml of 1N hydrochloric acid and THF evaporated under reducedpressure while the product starts to precipitate. The product isfiltered and dried under vacuum to yield 2.39 g (71% of theory) of awhite solid which is used in the next step without further purification.

[0226] b)(RS)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-(3RS)-carbonylchloride

[0227] A dispersion of 2.37 g (7.2 mmol) of(RS)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid in 50 ml of dichloromethane is treated with 3.1 ml (43.2 mmol) ofthionylchloride at RT during 18 h. For the working-up, the reactionmixture is evaporated under reduced pressure to dryness, then theresidue is dispersed in toluene and evaporated to dryness again to yieldquantitatively the acid chloride as a yellowish solid which is used inthe next step without further purification.

[0228] c)(3RS)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid (1R)-phenyl-ethyl ester

[0229] A solution of 2.49 g (7.2 mmol) of(RS)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-(3RS)-carbonylchloride in 42 ml of dichloromethane is prepared and cooled to 0° C. Thesolution of 0.73 g (6.0 mmol) of (R)-((+))-1-phenylethanol in a mixtureof 10 ml of dichloromethane and 0.48 ml pyridine is added dropwise.After complete addition, the reaction mixture is warmed to RT andstirring continued for 20 min. For the working-up, the reaction mixtureis evaporated under reduced pressure and 3.84 g of a yellowish solidresidue are obtained. For purification, the material obtained ischromatographed on silica gel by flas-chromatography using a gradient ofn-hexane to a 4:1 mixture of n-hexane and ethyl acetate as the eluent.There are obtained 1.96 g (76% of theory) of the mixture of the twodiastereomers as a white solid. MS: m/e=434 (M(+)H)⁽⁺⁾.

[0230] d)(3R)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid (1R)-phenyl-ethyl ester and(3S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid (1R)-phenyl-ethyl ester

[0231] The separation of 1.80 g (4.2 mmol) of the two isomers (Example24c) is performed on a preparative chiral HPLC column (CHIRALPAK® AD,pressure: 17 bar, flow: 35 ml/min) using a 4:1 mixture of n-heptane andethanol as the eluent. There are obtained 763 mg (42.4% of theory) ofthe first eluting isomer(3R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid (1R)-phenyl-ethyl ester [MS: m/e=434 (M⁽⁺⁾(+)H)] and 860 mg (47.8%of theory) of the later eluting isomer(3S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid (1R)-phenyl-ethyl ester [MS: m/e=434 (M(+)H)⁽⁺⁾], each as a whitesolid.

[0232] e)(R)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid

[0233] A solution of 0.622 g (1.44 mmol) of(3R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid (1R)-phenyl-ethyl ester in 17 ml of dioxane is treated with 1.68 mlof hydrochloric acid (37%) and the mixture is heated to 50° C. during 18h. For the work-up, the reaction mixture is evaporated under reducedpressure and the yellowish residue obtained is triturated with ethylacetate at −10° C. The mixture is filtered and the white solid driedunder vacuum to yield 344 mg (73% of theory) of the (R)-acid which isused in the next step without further purification. MS: m/e=328(M−H)⁽⁺⁾.

[0234] f)(R)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0235] A solution of 0.339 g (1.03 mmol) of(S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid in 21 ml of N,N-dimethylformamide, cooled to 0° C., is treatedconsecutively with 0.15 ml (1.13 mmol) of triethylamine, 0.390 g (1.03mmol) of HBTU, 0.085 g (1.24 mmol) of methylamine hydrochloride, and0.15 ml (1.13 mmol) of triethylamine. The reaction is stopped after 30min and the orange colored solution is evaporated under reducedpressure. The residue obtained is triturated in ethyl acetate, the whitesolid product is filtered, thereafter dissolved in dichloromethane andthe solution washed three times with water. The organic phase is driedover sodium sulfate, then evaporated under reduced pressure to yield 231mg (66% of theory) of a white solid. MS: m/e=343 (M(+)H)⁽⁺⁾;[α]₅89=−25.48° (c=0.954, CH₂Cl₂).

EXAMPLE 25(S)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0236] a)(S)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid

[0237] In an analogous manner to that described in Example 24e),starting from(3S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid (1R)-phenyl-ethyl ester (Example 24d) by acidic hydrolysis of theester there is obtained(S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid as a white solid which is used in the next step without furtherpurification. MS: m/e=328 (M−H)⁽⁺⁾.

[0238] b)(S)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0239] In an analogous manner to that described in Example 24f), bycondensing(S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid with methylamine using HBTU as the condensation agent there isobtained(S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide as a white solid. MS: mile=343 (M(+)H)⁽⁺⁾; [α]₅₈₉=(+)28.17° (c=0.831, CH₂Cl₂).

EXAMPLE 26 (R)-1-(4-Benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0240] a) (RS)-1-(4-Benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carbonylchloride

[0241] In an analogous manner to that described in Example 24b),starting from (RS)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylicacid (Example 1a) by treatment with thionylchloride there is obtained(RS)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carbonyl chloride as ayellowish solid which is directly used in the next step without furtherpurification.

[0242] b) (3R)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylicacid (1R)-phenyl-ethyl ester and(3S)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid(1R)-phenyl-ethyl ester

[0243] In an analogous manner to that described in Example 24c) and24d), starting from(RS)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carbonyl chloride byreaction with (R)-((+))-1-phenylethanol there is obtained the mixture ofthe two isomers(3RS)-1-(4-benzyl-oxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid(1R)-phenyl-ethyl ester which is separated on a preparative chiral HLPCcolumn (conditions see Example 24d) to yield the first eluting(3R)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid(1R)-phenyl-ethyl ester [MS: m/e=416 (M⁽⁺⁾(+)H)] and(3S)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid(1R)-phenyl-ethyl ester [MS:

[0244] m/e=416 (M(+)H)⁽⁺⁾] as a white solid each.

[0245] c) (3R)-1-(4-Benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylicacid

[0246] In an analogous manner to that described in Example 24e),starting from (3R)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylicacid (1R)-phenyl-ethyl ester by acidic hydrolysis of the ester there isobtained (3R)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acidas a white solid which is used in the next step without furtherpurification. MS: m/e=310 (M−H)⁽⁺⁾.

[0247] d) (R)-1-(4-Benzyloxy)-phenyl)-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0248] In an analogous manner to that described in Example 24f), bycondensing (R)-1-(4-benzyloxy)-phenyl)-5-oxo-pyrrolidine-3-carboxylicacid with methylamine using HBTU as the condensation agent there isobtained (R)-1-(4-benzyloxy)-phenyl)-5-oxo-pyrrolidine-3-carboxylic acidmethylamide as a white solid. MS: m/e=325 (M(+)H)⁽⁺⁾; [α]₅89=−27.55°(c=0.958, CH₂Cl₂).

EXAMPLE 27 (S)-1-(4-Benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0249] a) (RS)-1-(4-Benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carbonylchloride

[0250] In an analogous manner to that described in Example 24b),starting from (RS)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylicacid (Example 1a) by treatment with thionylchloride there is obtained(RS)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carbonyl chloride as ayellowish solid which is directly used in the next step without furtherpurification.

[0251] b) (3R)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylicacid (1R)-phenyl-ethyl ester and(3S)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid(1R)-phenyl-ethyl ester

[0252] In an analogous manner to that described in Example 24c and 24d,starting from (RS)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carbonylchloride by reaction with (R)-((+))-1-phenylethanol there is obtainedthe mixture of the two isomers(3RS)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid(1R)-phenyl-ethyl ester which is separated on a preparative chiral HLPCcolumn (CHIRALPAK® AD, pressure: 17 bar, flow: 35 ml/min) using a 4:1mixture of n-heptane and isopropanol as the eluent) to yield the firsteluting (3R)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid(1R)-phenyl-ethyl ester [MS: m/e=416 (M⁽⁺⁾(+)H)] and(3S)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid(1R)-phenyl-ethyl ester [MS: m/e=416 (M(+)H)⁽⁺⁾] as a white solid each.

[0253] c) (S)-1-(4-Benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid

[0254] In an analogous manner to that described in Example 24e, startingfrom (3S)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid(1R)-phenyl-ethyl ester by acidic hydrolysis of the ester there isobtained (3S)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acidas a white solid which is used in the next step without furtherpurification. MS: m/e=310 (M−H)⁽⁺⁾.

[0255] d) (S)-1-(4-Benzyloxy)-phenyl)-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0256] In an analogous manner to that described in Example 24f, bycondensing (S)-1-(4-benzyloxy)-phenyl)-5-oxo-pyrrolidine-3-carboxylicacid with methylamine using HBTU as the condensation agent there isobtained (S)-1-(4-benzyloxy)-phenyl)-5-oxo-pyrrolidine-3-carboxylic acidmethylamide as a white solid. MS: m/e=325 (M(+)H)⁽⁺⁾; [α]₅₈₉ =(+)32.02°(c=1.037, CH₂Cl₂).

EXAMPLE 28(R)-1-[4-(4-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0257] a) (R)-1-(4-Hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acidmethyl ester

[0258] A suspension of 2.51 g (10.6 mmol) of(RS)-1-(4-hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methylester in 10 ml of phosphate buffer [c(KH₂PO₄)=0.05 mol/l], 25 ml ofsodium sulfate solution [c(Na₂SO₄)=4 mol/l], 45 ml of deionised water,and 20 ml of tert-butylmethylether is adjusted to pH 6.0. Under moderatestirring, 51.3 mg of cholesterase from Candida cylindracea (RocheApplied Science, Industrial Products, Enzyme Projects, Sandhofer Str.116, D-68305 Mannheim, Germany, order no. 10129046103) are added insolid form. By an automatic pH-Stat-System, the pH is kept constant at6.0 by addition of sodium hydroxide solution [c(NaOH)=1.0 mol/l] at RT.The progress of the reaction is followed by the consumption of sodiumhydroxide solution. After the addition of 5.21 ml of sodium hydroxidesolution, the reaction is stopped by addition of dichloromethane. Theorganic layer is separated, then washed three times with water,thereafter, dried over sodium sulfate, and finally evaporated. The crudeester is a slightly rose oil which after trituration intert-butylmethylether at RT is obtained as a white solid. The product iscollected on a filter funnel and yields after drying under high vacuumat RT 1.11 g (44.3% of theory) of(R)-1-(4-hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methylester; m.p.: 122.9° C.; optical integrity: 97.9% e.e.; [α]²⁰ _(D)=−35.2(c=1.162g/100 ml CHCl₃).

[0259] b)(R)-1-[4-(4-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methyl ester

[0260] A solution of 550 mg (4.3 mmol) of 4-fluoro-benzylalcohol and1.27 g (4.7 mmol) of triphenylphosphine in 7 ml of tetrahydrofurane isadded dropwise at 0° C. to a solution of 1.11 g (4.7 mmol) of(R)-1-(4-hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methylester and 1.01 g (4.7 mmol) of diisopropyl azodicarboxylate in 11 ml oftetrahydrofurane. The mixture is left to warm to RT and stirring iscontinued for 18 hours. For the working-up, after addition of 2 g ofsilica gel the reaction mixture is evaporated under reduced pressure.For purification, the material obtained is chromatographed on silica gelusing first a 2:1-mixture, then a 1:1-mixture of heptane and ethylacetate as the eluent. There are obtained 1.39 g (95% of theory) of(R)-1-[4-(4-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methyl ester as a white solid; MS: m/e=344 (M(+)H)⁽⁺⁾.

[0261] c)(R)-1-[4-(4-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid

[0262] A solution of 1.27 g (3.7 mmol) of(R)-1-[4-(4-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methyl ester in 77 ml of dioxane is treated with 8.64 ml ofhydrochloric acid (37%). The mixture is heated at 52° C. for 18 h in aclosed flask. For the working-up, the solution is evaporated underreduced pressure to yield the crude acid as a yellowish solid. Forpurification, the crude acid is triturated at −5° C. in 10 ml of ethylacetate. The solid is collected on a filter funnel and then dried underhigh vacuum to yield 0.624 g (51% of theory) of(R)-1-[4-(4-fluoro-benzyloxy) -phenyl]-5-oxo-pyrrolidine-3-carboxylicacid as a white solid; MS: m/e=330 (M(+)H)⁽⁺⁾.

[0263] d)(R)-1-[4-(4-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0264] In an analogous manner to that described in Example 24 f), bycondensing the(R)-1-[4-(4-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid with methylamine using HBTU as the condensation agent the(R)-1-[4-(4-fluoro-benzyloxy) -phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide is obtained as a white solid. MS: m/e=343 (M(+)H)⁽⁺⁾.

EXAMPLE 29(R)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide (cf. Example 24)

[0265] a)(R)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methyl ester

[0266] In an analogous manner to that described in Example 28b), thealkylation of the(R)-1-(4-hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methylester [Example 28a)] with 3-fluorobenzylalcohol yields the(R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methyl ester as a white solid. MS: m/e=344 (M(+)H)⁽⁺⁾.

[0267] b)(R)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid

[0268] In an analogous manner to that described in Example 28c), theacidic hydrolysis of the(R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methyl ester yields the(R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid as a white solid. MS: m/e=328 (M(+)H)⁽⁺⁾.

[0269] c)(R)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0270] In an analogous manner to that described in Example 24 f), thecondensation of the(R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid with methylamine using HBTU as the condensation agent yields the(R)-1-[4-(3-fluoro-benzyloxy) -phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide as a white solid. MS: m/e=343 (M(+)H)⁽⁺⁾.

EXAMPLE 30(R)-1-[4-(3-Chloro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0271] a)®-1-[4-(3-Chloro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acidmethyl ester

[0272] In an analogous manner to that described in Example 28b), thealkylation of the ®-1-(4-hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylicacid methyl ester [Example 28a)] with 3-chlorobenzylalcohol yields the®-1-[4-(3-chloro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acidmethyl ester as a white solid. MS: m/e=360 (M(+)H)⁽⁺⁾.

[0273] b)(R)-1-[4-(3-Chloro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid

[0274] In an analogous manner to that described in Example 28c), theacidic hydrolysis of the(R)-1-[4-(3-chloro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methyl ester yields the(R)-1-[4-(3-chloro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid as a white solid. MS: m/e=344 (M(+)H)⁽⁺⁾.

[0275] c)(R)-1-[4-(3-Chloro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0276] In an analogous manner to that described in Example 24f), thecondensation of the(R)-1-[4-(3-chloro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid with methylamine using HBTU as the condensation agent yields the(R)-1-[4-(3-chloro-benzyloxy) -phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide as a white solid. MS: m/e=359 (M(+)H)⁽⁺⁾.

EXAMPLE 31(R)-1-[4-(2,6-Difluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0277] a)(R)-1-[4-(2,6-Difluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methyl ester

[0278] In an analogous manner to that described in Example 28b), thealkylation of the(R)-1-(4-hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methylester [Example 28a)] with 2,6-difluorobenzylalcohol yields the(R)-1-[4-(2,6-difluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methyl ester as a white solid. MS: m/e=362 (M(+)H)⁽⁺⁾.

[0279] b)(R)-1-[4-(2,6-Difluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid

[0280] In an analogous manner to that described in Example 28c), theacidic hydrolysis of the(R)-1-[4-(2,6-difluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methyl ester yields the(R)-1-[4-(2,6-difluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid as a white solid. MS: m/e=346 (M(+)H)⁽⁺⁾.

[0281] c)(R)-1-[4-(2,6-Difluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0282] In an analogous manner to that described in Example 24f), thecondensation of the(R)-1-[4-(2,6-difluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid with methylamine using HBTU as the condensation agent yields the(R)-1-[4-(2,6-difluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide as a white solid. MS: m/e=361 (M(+)H)⁽⁺⁾.

EXAMPLE 32(R)-5-Oxo-1-[4-(2,4,6-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methylamide

[0283] a)(R)-5-Oxo-1-[4-(2,4,6-Trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methyl ester

[0284] In an analogous manner to that described in Example 28b), thealkylation of the(R)-1-(4-hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methylester [Example 28a)] with 2,4,6-trifluorobenzylalcohol yields the(R)-5-oxo-1-[4-(2,4,6-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylic acid methyl ester as a white solid.MS:

[0285] m/e=380 (M(+)H)⁽⁺⁾.

[0286] b)(R)-5-Oxo-1-[4-(2,4,6-Trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid

[0287] In an analogous manner to that described in Example 28c), theacidic hydrolysis of the(R)-5-oxo-1-[4-(2,4,6-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methyl ester yields the(R)-5-oxo-1-[4-(2,4,6-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid as a white solid. MS: m/e=364 (M(+)H)⁽⁺⁾.

[0288] c)(R)-5-Oxo-1-[4-(2,4,6-Trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methylamide

[0289] In an analogous manner to that described in Example 24 f), thecondensation of the(R)-5-oxo-1-[4-(2,4,6-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid with methylamine using HBTU as the condensation agent yields the(R)-5-Oxo-1-[4-(2,4,6-Trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methylamide as a white solid. MS: m/e=379 (M(+)H)⁽⁺⁾.

EXAMPLE 33(RS)-1-[4-(3,4-Difluoro-benzyloxy)-phenyl[-5-oxo-pyrrolidin-3-yl]-aetonitrile

[0290] a)(RS)-1-[4-(3,4-Difluoro-benzyloxy)-phenyl]-4-hydroxymethyl-pyrrolidin-2-one

[0291] 2.0 g (5.54 mmol)(RS)-1-[4-(3,4-Difluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methyl ester is dissolved in 50 ml THF. 1.05 g (27.7 mmol) ofsodium borohydride is added and the reaction mixture boiled under refluxfor 24 hours. Water is added and the product is extracted with ethylacetate to yield 1.68 g (91%) of a yellowish solid. MS: m/e=334.3(M(+)H)⁽⁺⁾.

[0292] b)(RS)-1-[4-(3,4-Difluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetonitrile

[0293] 300 mg (0.9 mmol)(RS)-1-[4-(3,4-Difluoro-benzyloxy)-phenyl]-4-hydroxymethyl-pyrrolidin-2-oneand 0.136 mg (1.35 mmol) triethylamine are dissolved in 20 mldichloromethane and cooled to 0° C. 155 mg (1.35 mmol) methanesulfonylchloride is added. The mixture is stirred at 0° C. for 30 min then at RTfor 3 hours, then washed successively with water, 1 M hydrochloric acid,10% sodium hydrogen carbonate and saturated sodium chloride solution.Drying and evaporation gives the crude mesylate, which is dissolved in 2ml N,N-dimethylformamide. 110 mg (2.25 mmol) sodium cyanide is added andthe reaction mixture is hold at 1001° C. for 24 hours. Hydrolysis andextraction with ethyl acetate gives the crude nitrile, which issubjected to chromatography (silica gel, dichloromethane/methanol).Yield: 20% of a brownish solid. MS: m/e=343.1 (M(+)H)⁽⁺⁾.

EXAMPLE 34(RS)-{1-[4-(3-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetonitrile

[0294] a)(RS)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-4-hydroxymethyl-pyrrolidin-2-one

[0295] The title compound is prepared in analogy to Example 33a) from(RS)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methyl ester and sodium borohydride. Yield: 82% of a colorlesssolid. MS: m/e=316.3 (M(+)H)⁽⁺⁾.

[0296] b)(RS)-{1-[4-(3-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetonitrile

[0297] The title compound is prepared in analogy to Example 33b) from(RS)-1-[4-(3-fluoro-benzyloxy)-phenyl]-4-hydroxymethyl-pyrrolidin-2-one,methanesulfonyl chloride and sodium cyanide. Yield: 27% of a colorlesssolid. MS: m/e=325.2 (M(+)H)⁽⁺⁾.

EXAMPLE 35(RS)-[1-(4-Benzyloxy-phenyl)-5-oxo-pyrrolidin-3-yl]-acetonitrile

[0298] a) (RS)-1-(4-Benzyloxy-phenyl)-4-hydroxymethyl-pyrrolidin-2-one

[0299] The title compound is prepared in analogy to Example 33a) from(RS)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methylester and sodium borohydride. Yield: 82% of a colorless solid. MS:m/e=298.3 (M(+)H)⁽⁺⁾.

[0300] b) (RS)-1-(4-Benzyloxy-phenyl)-4-chloromethyl-pyrrolidin-2-one

[0301] 740 mg (2.49 mmol)(RS)-1-(4-benzyloxy-phenyl)-4-hydroxymethyl-pyrrolidin-2-one isdissolved in 20 ml toluene. 1.08 ml (14.9 mmol) thionyl chloride isadded and the mixture refluxed for 6 hours. Evaporation andchromatography (silica gel, n-hexane/ethyl acetate 1:1) yields 123 mg(16%) of a brownish semisolid. MS: m/e=315.2 (M(+)).

[0302] c)(RS)-[1-(4-Benzyloxy-phenyl)-5-oxo-pyrrolidin-3-yl]-acetonitrile

[0303] 123 mg (0.39 mmol)(RS)-1-(4-benzyloxy-phenyl)-4-chloromethyl-pyrrolidin-2-one is dissolvedin 2.5 ml N,N-dimethylformamide. After addition of 29 mg (0.58 mmol)sodium cyanide and 6 mg (0.04 mmol) sodium iodide, the mixture is holdat 120° C. for 15 min. Dilution with water and extraction with ethylacetate yields 44 mg (37%) of a brownish solid. MS: m/e=307.3(M(+)H)⁽⁺⁾.

EXAMPLE 36(RS)-(E)-1-{4-[2-(3-Fluoro-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0304] a) (E)-1-Fluoro-3-[2-(4-nitrophenyl)ethenyl]-benzene

[0305] A suspension of 677 mg of sodium hydride (55% dispersion in oil)in 10 ml of N,N-dimethylformamide are cooled to 0° C. Thereupon, 5.61 g(20.5 mmol) of diethyl (4-nitrobenzyl)phosphonate are added portionwise.The reaction mixture is left to warm to RT and stirred for 1.5 hours.Thereafter, the mixture is cooled to −101° C. and a solution of 1.5 g(12.1 mmol) of 3-fluorobenzaldehyde in 5 ml N,N-dimethylformamide isadded dropwise. Stirring is continued for 30 min at 0° C., then at RT.For the working-up, ice and ethyl acetate is added to the reactionmixture. The organic layer is separated, dried over magnesium sulfateand evaporated under reduced pressure to yield the crude crystallineproduct, which after recrystallisation from a mixture of ether andheptane gives 2.41 g (82% of theory) of(E)-1-fluoro-3-[2-(4-nitrophenyl)ethenyl]-benzene as a yellow solid; MS:m/e=243(M)⁽⁺⁾.

[0306] b) (E)-4-[2-(3-Fluoro-phenyl)-vinyl]-phenylamine

[0307] A solution of 2.41 g (10 mmol)(E)-1-fluoro-3-[2-(4-nitrophenyl)ethenyl]-benzene in 25 ml of ethylacetate is flushed with argon and, thereafter, hydrogenated at RT andatmospheric pressure during 4 hours using 0.241 g of platinum on carbon(5%) as the catalyst. For the working-up, the catalyst is filtered overDicalit and the resulting solution is evaporated under reduced pressure.The solid material obtained is crystallised from a mixture of ether andheptane to yield 1.32 g (62.5% of theory) of(E)-4-[2-(3-fluoro-phenyl)-vinyl]-phenylamine as an orange solid; MS:m/e=213 (M)⁽⁺⁾.

[0308] c)(RS)-(E)-1-{4-[2-(3-Fluoro-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid

[0309] A mixture of 600 mg (2.8 mmol) of(E)-4-[2-(3-fluoro-phenyl)-vinyl]-phenylamine and 366 mg (2.8 mmol) ofitaconic acid is heated to 130° C. After 1 hour, the molten material iscooled to RT and, thereafter, the resulting solid is triturated withethyl acetate to yield 568 mg (62% of theory) of(RS)-(E)-1-{4-[2-(3-fluoro-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid as a fine yellow powder; MS:

[0310] m/e=324 (M−H)⁽⁺⁾.

[0311] d)(RS)-(E)-1-{4-[2-(3-Fluoro-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0312] A suspension of 300 mg (0.92 mmol) of(E)-1-{4-[2-(3-fluoro-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid in 5 ml of dichloromethane is treated with 549 mg (4.6 mmol) ofthionylchloride and heated to 45° C. for 18 hours. Thereafter, thereaction mixture is evaporated to dryness under reduced pressure. Thecrude acid chloride obtained is dissolved in 5 ml of drydichloromethane, then, at RT, 0.58 ml (4.61 mmol) of a solution ofmethylamine in ethanol (33%) is added and stirring continued for 3hours. For the working-up, the reaction mixture is treated with waterand dichloromethane. The organic layer is separated, dried overmagnesium sulfate and evaporated. For purification, the crude product ischromatographed on silica gel using a 95:5-mixture of dichloromethaneand methanol as the eluent. After crystallization from a mixture ofdichloromethane and ether, there are obtained 207 mg (66% of theory) of(RS)-(E)-1-{4-[2-(3-fluoro-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid methylamide as alight brown solid; MS: m/e=339 (M(+)H)⁽⁺⁾.

EXAMPLE 37(RS)-(E)-1-{4-[2-(4-Methoxy-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0313] a) (E)-1-Methoxy-4-[2-(4-nitrophenyl)ethenyl]-benzene

[0314] In an analogous manner to that described in Example 36a), thereaction of diethyl (4-nitrobenzyl)phosphonate with4-methoxybenzaldehyde yields the(E)-1-methoxy-4-[2-(4-nitrophenyl)ethenyl]-benzene as a yellow solid;MS: m/e=255 (M(+)H)⁽⁺⁾.

[0315] b) (E)-4-[2-(4-Methoxy-phenyl)-vinyl]-phenylamine

[0316] A mixture of 10.1 g (40 mmol) of(E)-1-methoxy-4-[2-(4-nitrophenyl)ethenyl]-benzene in 70 ml of ethanoland 130 ml of hydrochloric acid (25%) is heated to 110° C. Portionwise,15 g of tin are added and stirring is continued for 4.5 hours at 110° C.For the working-up, the reaction mixture is cooled and neutralised witha solution of sodium hydroxide. The mixture is transferred to aseparatory funnel where it is extracted with dichloromethane. Theorganic layer is separated, dried over sodium sulfate and evaporated.The residue is triturated in ether and, thereafter, the remaining solidis collected on a filter funnel. There are obtained 6.15 g (69% oftheory) of (E)-4-[2-(4-methoxy-phenyl)-vinyl]-phenylamine as a yellowcrystals; MS: m/e=226 (M(+)H)⁽⁺⁾.

[0317] c)(RS)-(E)-1-{4-[2-(4-Methoxy-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid

[0318] In an analogous manner to that described in Example 36 c), thereaction of (E)-4-[2-(4-methoxy-phenyl)-vinyl]-phenylamine with itaconicacid yields the(RS)-(E)-1-{4-[2-(4-methoxy-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid as a brown solid; MS: m/e=336 (M−H)⁽⁺⁾.

[0319] d)(RS)-(E)-1-{4-[2-(4-Methoxy-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methyl ester

[0320] A solution of 700 mg (2.1 mmol) of(RS)-(E)-1-{4-[2-(4-methoxy-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid in 7 ml of dichloromethane and 0.7 ml of methanol is treated with 1drop of sulfuric acid and heated at 40° C. for 20 hours. For theworking-up, the solvent is evaporated, thereafter, the residue istreated with water and ethyl acetate. The organic layer is separated,dried over magnesium sulfate, and evaporated under reduced pressure.After crystallization from ether of the crude ester, 584 mg (80% oftheory) of(RS)-(E)-1-{4-[2-(4-methoxy-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methyl ester are obtained as a light brown solid; MS: m/e=352(M(+)H)⁽⁺⁾.

[0321] e)(RS)-(E)-1-{4-[2-(4-Methoxy-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0322] A solution of 400 mg (1.1 mmol) of(RS)-(E)-1-{4-[2-(4-methoxy-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methyl ester in 1.4 ml of a solution of methylamine in ethanol(33%) is heated at 90° C. for 18 h in a sealed vial. For the working-up,the cooled solution is treated with water to precipitate the product.The solid material is collected on a filter funnel, washed with water,finally, with heptane. After crystallization of the crude amide from amixture of N,N-dimethylformamide and methanol, 98 mg (25% of theory) of(RS)-(E)-1-{4-[2-(4-methoxy-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methylamide are obtained as a light brown solid; MS: m/e=351(M(+)H)⁽⁺⁾.

EXAMPLE 38(RS)-(E)-1-{4-[2-(3-Methoxy-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0323] a) (E)-1-Methoxy-3-[2-(4-nitrophenyl)ethenyl]-benzene

[0324] In an analogous manner to that described in Example 36a), thereaction of diethyl (4-nitrobenzyl)phosphonate with3-methoxybenzaldehyde yields the(E)-1-methoxy-3-[2-(4-nitrophenyl)ethenyl]-benzene as a yellow solid;MS: m/e=255 (M(+)H)⁽⁺⁾.

[0325] b) (E)-4-[2-(4-Methoxy-phenyl)-vinyl]-phenylamine

[0326] In an analogous manner to that described in Example 37b), thereduction of (E)-1-methoxy-3-[2-(4-nitrophenyl)ethenyl]-benzene usingtin yields the (E)-4-[2-(3-methoxy-phenyl)-vinyl]-phenylamine as a brownoil; MS: m/e=226 (M(+)H)⁽⁺⁾.

[0327] c)(RS)-(E)-1-{4-[2-(3-Methoxy-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid

[0328] In an analogous manner to that described in Example 36 c), thereaction of (E)-4-[2-(3-methoxy-phenyl)-vinyl]-phenylamine with itaconicacid yields the(RS)-(E)-1-{4-[2-(3-methoxy-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid as a brown solid; MS: m/e=336 (M−H)⁽⁺⁾.

[0329] d)(RS)-(E)-1-{4-[2-(3-Methoxy-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methyl ester

[0330] In an analogous manner to that described in Example 37 d), theesterification of(RS)-(E)-1-{4-[2-(3-methoxy-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid yields the(RS)-(E)-1-{4-[2-(3-methoxy-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methyl ester as a brown solid; MS: m/e=352 (M(+)H)⁽⁺⁾.

[0331] e)(RS)-(E)-1-{4-[2-(3-Methoxy-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0332] In an analogous manner to that described in Example 37 e), theaminolysis of(RS)-(E)-1-{4-[2-(3-methoxy-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methyl ester yields the(RS)-(E)-1-{4-[2-(3-methoxy-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methylamide as a light yellow solid; MS: m/e=351 (M(+)H)⁽⁺⁾.

EXAMPLE 39(RS)-(E)-1-{4-[2-(4-Fluoro-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0333] a) (E)-1-Fluoro-4-[2-(4-nitrophenyl)ethenyl]-benzene

[0334] In an analogous manner to that described in Example 36 a), thereaction of diethyl (4-nitrobenzyl)phosphonate with 4-fluorobenzaldehydeyields the (E)-1-fluoro-4-[2-(4-nitrophenyl)ethenyl]-benzene as a yellowcrystalline solid; MS: m/e=243 (M)⁽⁺⁾.

[0335] b) (E)-4-[2-(4-Fluoro-phenyl)-vinyl]-phenylamine

[0336] In an analogous manner to that described in Example 37 b), thereduction of (E)-1-fluoro-3-[2-(4-nitrophenyl)ethenyl]-benzene with tinyields the (E)-4-[2-(4-fluoro-phenyl) -vinyl]-phenylamine as a whitesolid; MS: 214 (M(+)H)⁽⁺⁾.

[0337] c)(RS)-(E)-1-{4-[2-(4-Fluoro-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid

[0338] In an analogous manner to that described in Example 36 c), thereaction of (E)-4-[2-(4-fluoro-phenyl)-vinyl]-phenylamine with itaconicacid yields the(RS)-(E)-1-{4-[2-(4-fluoro-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid which was directly engaged in the next step without furtherpurification and characterisation.

[0339] d)(RS)-(E)-1-{4-[2-(4-Fluoro-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methyl ester

[0340] In an analogous manner to that described in Example 37 d), theesterification of(RS)-(E)-1-{4-[2-(4-fluoro-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid yields the(RS)-(E)-1-{4-[2-(4-fluoro-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methyl ester.

[0341] e)(RS)-(E)-1-{4-[2-(4-Fluoro-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0342] In an analogous manner to that described in Example 37 e), theaminolysis of (RS)-(E)-1-{4-[2-(4-fluoro-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methyl ester yields the(RS)-(E)-1-{4-[2-(4-fluoro-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methylamide as a white solid; MS: m/e=339 (M(+)H)⁽⁺⁾.

EXAMPLE 40(RS)-1-{4-[2-(3-Chloro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0343] a) (E)-1-Chloro-3-[2-(4-nitrophenyl)ethenyl]-benzene

[0344] In an analogous manner to that described in Example 36 a), thereaction of diethyl (4-nitrobenzyl)phosphonate with 3-chlorobenzaldehydeyields the (E)-1-chloro-3-[2-(4-nitrophenyl)ethenyl]-benzene as anorange crystalline solid; MS: m/e=259 (M)⁽⁺⁾.

[0345] b) 4-[2-(3-Chloro-phenyl)-ethyl]-phenylamine

[0346] In an analogous manner to that described in Example 36 b), thehydrogenation of (E)-1-chloro-3-[2-(4-nitrophenyl)ethenyl]-benzene usingplatinum on carbon (5%) as the catalyst but with a reaction time of 18hours and simultaneous reduction of the double bond yields the4-[2-(3-chloro-phenyl)-ethyl]-phenylamine as a dark brown oil; MS:m/e=232 (M(+)H)⁽⁺⁾.

[0347] c)(RS)-1-{4-[2-(3-Chloro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid

[0348] In an analogous manner to that described in Example 36 c), thereaction of 4-[2-(3-chloro-phenyl)-ethyl]-phenylamine with itaconic acidyields the(RS)-1-{4-[2-(3-chloro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid as an off-white solid; MS: m/e=342 (M−H)⁽⁺⁾.

[0349] d)(RS)-1-{4-[2-(3-Chloro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methyl ester

[0350] In an analogous manner to that described in Example 37 d), theesterification of(RS)-1-{4-[2-(3-chloro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid yields the(RS)-1-{4-[2-(3-chloro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methyl ester as a white solid; MS: m/e=358 (M(+)H)⁽⁺⁾.

[0351] e)(RS)-(E)-1-{4-[2-(3-Chloro-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0352] In an analogous manner to that described in Example 37 e), theaminolysis of(RS)-1-{4-[2-(3-chloro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methyl ester yields the(RS)-1-{4-[2-(3-chloro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methylamide as a light yellow solid; MS: m/e=357 (M(+)H)⁽⁺⁾.

EXAMPLE 41(RS)-1-{4-[2-(4-Chloro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0353] a) (E)-1-Chloro-4-[2-(4-nitrophenyl)ethenyl]-benzene

[0354] In an analogous manner to that described in Example 36 a), thereaction of diethyl (4-nitrobenzyl)phosphonate with 4-chlorobenzaldehydeyields the (E)-1-chloro-4-[2-(4-nitrophenyl)ethenyl]-benzene as anyellow crystalline solid; MS: m/e=259 (M)⁽⁺⁾.

[0355] b) 4-[2-(4-Chloro-phenyl)-ethyl]-phenylamine

[0356] In an analogous manner to that described in Example 36 b), thehydrogenation of (E)-1-chloro-4-[2-(4-nitrophenyl)ethenyl]-benzene usingplatinum on carbon (5%) as the catalyst but with a reaction time of 18hours and simultaneous reduction of the double bond yields the4-[2-(4-chloro-phenyl)-ethyl]-phenylamine as a light yellow solid; MS:m/e=232 (M(+)H)⁽⁺⁾.

[0357] c)(RS)-1-{4-[2-(4-Chloro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid

[0358] In an analogous manner to that described in Example 36 c), thereaction of 4-[2-(4-chloro-phenyl)-ethyl]-phenylamine with itaconic acidyields the(RS)-1-{4-[2-(4-chloro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid as an off-white solid; MS: m/e=342 (M−H)⁽⁺⁾.

[0359] d)(RS)-1-{4-[2-(4-Chloro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methyl ester

[0360] In an analogous manner to that described in Example 37 d), theesterification of(RS)-1-{4-[2-(4-chloro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid yields the(RS)-1-{4-[2-(4-chloro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methyl ester as a white solid; MS: m/e=357 (M)⁽⁺⁾.

[0361] e)(RS)-(E)-1-{[4-[2-(4-Chloro-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0362] In an analogous manner to that described in Example 37 e), theaminolysis of(RS)-1-{4-[2-(4-chloro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methyl ester yields the(RS)-1-{4-[2-(4-chloro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methylamide as a white solid; MS: m/e=357 (M(+)H)⁽⁺⁾.

EXAMPLE 42(RS)-1-{4-[2-(3-Fluoro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0363] a) 4-[2-(3-Fluoro-phenyl)-ethyl]-phenylamine

[0364] In an analogous manner to that described in Example 36 b), thehydrogenation of (E)-1-fluoro-3-[2-(4-nitrophenyl)ethenyl]-benzene[Example 36 a)] using palladium on carbon (10%) as the catalyst yieldsthe 4-[2-(3-fluoro-phenyl)-ethyl]-phenylamine as a yellow solid; MS:m/e=215 (M)⁽⁺⁾.

[0365] b)(RS)-1-{4-[2-(3-Fluoro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid

[0366] In an analogous manner to that described in Example 36 c), thereaction of 4-[2-(3-fluoro-phenyl)-ethyl]-phenylamine with itaconic acidyields the(RS)-1-{4-[2-(3-fluoro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid as a light brown solid; MS: m/e=326 (M−H)⁽⁺⁾.

[0367] c)(RS)-(E)-1-{4-[2-(3-Fluoro-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0368] In an analogous manner to that described in Example 36 d), theesterification of(RS)-1-{4-[2-(3-fluoro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid and reaction of the intermediate acid chloride with methylamineyields the(RS)-1-{4-[2-(3-fluoro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methylamide as a light yellow solid; MS: m/e=341 (M(+)H)⁽⁺⁾.

EXAMPLE 43(RS)-1-{4-[2-(4-Fluoro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0369] a) 4-[2-(4-Fluoro-phenyl)-ethyl]-phenylamine

[0370] In an analogous manner to that described in Example 36 b), thehydrogenation of (E)-1-fluoro-4-[2-(4-nitrophenyl)ethenyl]-benzene[Example 39 a)] using palladium on carbon (10%) as the catalyst yieldsthe 4-[2-(4-fluoro-phenyl)-ethyl]-phenylamine as a light red solid; MS:m/e=216 (M(+)H)⁽⁺⁾.

[0371] b)(RS)-1-{4-[2-(4-Fluoro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid

[0372] In an analogous manner to that described in Example 36 c), thereaction of 4-[2-(4-fluoro-phenyl)-ethyl]-phenylamine with itaconic acidyields the(RS)-1-{4-[2-(4-fluoro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid as a white solid; MS: m/e=326 (M−H)⁽⁺⁾.

[0373] c)(RS)-1-{4-[2-(4-Fluoro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methyl ester

[0374] In an analogous manner to that described in Example 37 d), theesterification of(RS)-1-{4-[2-(4-fluoro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid yields the(RS)-1-{4-[2-(4-fluoro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methyl ester as a white solid; MS: m/e=342 (M(+)H)⁽⁺⁾.

[0375] d)(RS)-(E)-1-{4-[2-(4-Fluoro-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0376] In an analogous manner to that described in Example 37 e), theaminolysis of(RS)-1-{4-[2-(4-fluoro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methyl ester yields the(RS)-1-{4-[2-(4-fluoro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methylamide as a light brown solid; MS: m/e=341 (M(+)H)⁽⁺⁾.

EXAMPLE 44(RS)-1-[4-[2-(3Methoxy-phenyl)-ethyl]-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0377] a) 4-[2-(3-Methoxy-phenyl)-ethyl]-phenylamine

[0378] In an analogous manner to that described in Example 36 b), thehydrogenation of (E)-1-fluoro-4-[2-(4-nitrophenyl)ethenyl]-benzene[Example 38 a)] using palladium on carbon (10%) as the catalyst yieldsthe 4-[2-(3-methoxy-phenyl)-ethyl]-phenylamine as a light red solid; MS:m/e=228 (M(+)H)⁽⁺⁾.

[0379] b)(RS)-1-{4-[2-(3-Methoxy-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid

[0380] In an analogous manner to that described in Example 36 c), thereaction of 4-[2-(3-methoxy-phenyl)-ethyl]-phenylamine with itaconicacid yields the(RS)-1-{4-[2-(3-methoxy-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid as a white solid; MS: m/e=338 (M−H)⁽⁺⁾.

[0381] c)(RS)-1-{4-[2-(3Methoxy-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methyl ester

[0382] In an analogous manner to that described in Example 37 d), theesterification of(RS)-1-{4-[2-(3-methoxy-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid yields the(RS)-1-{4-[2-(3-methoxy-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methyl ester as a light yellow oil; MS: m/e=354 (M(+)H)⁽⁺⁾.

[0383] d)(RS)-(E)-1-{4-[2-(3-Methoxy-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0384] In an analogous manner to that described in Example 37 e), theaminolysis of(RS)-1-{4-[2-(3-methoxy-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methyl ester yields the(RS)-1-{4-[2-(3-methoxy-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methylamide as a white solid; MS: m/e=353 (M(+)H)⁽⁺⁾.

EXAMPLE 45(RS)-1-[6-(4-Fluoro-benzyloxy)-pyridin-3-yl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0385] a) 2-(4-Fluoro-benzyloxy)-5-nitro-pyridine

[0386] In an analogous manner to that described in J. Medicinal Chem.33:2087-93 (1990), the reaction 4-fluorobenzylalcohol instead ofbenzylalcohol with 2-chloro-5-nitropyridine yields the2-(4-fluoro-benzyloxy)-5-nitro-pyridine as a yellow solid.

[0387] b) 6-(4-Fluoro-benzyloxy)-pyridin-3-ylamine

[0388] A mixture of 0.70 g (2.8 mmol) of2-(4-fluoro-benzyloxy)-5-nitro-pyridine and 2.36 g (4.2 mmol) of ironpowder in 35 ml of water and 0.7 ml of acetic acid is heated underreflux for 4 hours. For the working-up, the reaction mixture is treatedunder vigorous stirring with water and ethyl acetate, thereafter,filtered over a layer of Dicalit. The organic layer is separated, driedover sodium sulfate and evaporated under reduced pressure. There areobtained 0.28 g (45% of theory) of 6-(4-fluoro-benzyloxy)-pyridin-3-ylamine as a greenish solid which is engaged in the next stepwithout further purification.

[0389] c)(RS)-1-[6-(4-Fluoro-benzyloxy)-pyridin-3-yl]-5-oxo-pyrrolidine-3-carboxylicacid

[0390] In an analogous manner to that described in Example 36 c), thereaction of 6-(4-fluoro-benzyloxy)-pyridin-3-ylamine with itaconic acidyields the crude(RS)-1-[6-(4-fluoro-benzyloxy)-pyridin-3-yl]-5-oxo-pyrrolidine-3-carboxylicacid as a green solid (yield 47% of theory).

[0391] d)(RS)-1-[6-(4-Fluoro-benzyloxy)-pyridin-3-yl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide

[0392] A solution of 105 mg (0.3 mmol) of(RS)-1-[6-(4-fluoro-benzyloxy)-pyridin-3-yl]-5-oxo-pyrrolidine-3-carboxylicacid in 5 ml N,N-dimethylformamide is treated with 58 mg (0.35 mmol) ofN,N-carbonyl-diimidazole, and the mixture is stirred at RT for 15 min.Thereafter, 26 mg (0.38 mmol) of methylamine hydrochloride and 50 μl(0.35 mmol) of triethylamine are added. After 30 min, the solvent isevaporated under reduced pressure and the residue is chromatographed onsilica gel using a 98:2-mixture of dichloromethane and methanol as theeluent. There are obtained 15 mg (15% of theory) of(RS)-1-[6-(4-fluoro-benzyloxy)-pyridin-3-yl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide as a green oil which solidifies on standing. MS:m/e=344 (M(+)H)⁽⁺⁾.

[0393] The following Examples A to D are prophetic.

EXAMPLE A Tablets

[0394] Tablets of the following composition are produced in aconventional manner: mg/Tablet Active ingredient 100 Powdered lactose 95 White corn starch  35 Polyvinylpyrrolidone  8 Na carboxymethylstarch 10 Magnesium stearate  2 Tablet weight 250

[0395] Tablets of the following composition are produced in aconventional manner: mg/Tablet Active ingredient 200 Powdered lactose100 White corn starch  64 Polyvinylpyrrolidone  12 Nacarboxymethylstarch  20 Magnesium stearate  4 Tablet weight 400

EXAMPLE C Capsules

[0396] Capsules of the following composition are produced: mg/CapsuleActive ingredient  50 Crystalline lactose  60 Microcrystalline cellulose 34 Talc  5 Magnesium stearate  1 Capsule fill weight 150

[0397] The active ingredient having a suitable particle size, thecrystalline lactose and the microcrystalline cellulose are homogeneouslymixed with one another, sieved and thereafter talc and magnesiumstearate are admixed. The final mixture is filled into hard gelatinecapsules of suitable size.

EXAMPLE D Injection Solution

[0398] An injection solution may have the following composition and ismanufactured in usual manner: Active substance  1.0 mg 1 N HCl 20.0 μlacetic acid  0.5 mg NaCl  8.0 mg phenol 10.0 mg 1 N NaOH q.s. ad pH 5H₂O q.s. ad 1 ml

1. A compound of the formula I

wherein Q is ═N— or ═C(R²⁴)—; X—Y is —CH₂—CH₂—, —CH═CH— or —CH₂—O—; R¹,R^(1.1) and R^(1.2) independently from each other are selected from thegroup consisting of hydrogen, halogen, (C₁-C₆)-alkyl,halogen-(C₁-C₆)-alkyl, cyano, (C₁-C₆)-alkoxy or halogen-(C₁-C₆)-alkoxy;R²¹, R²² and R²³ independently from each other are selected from thegroup consisting of hydrogen and halogen; R²⁴ is hydrogen, halogen ormethyl; R³ is —C(O)N(H)CH₃ or —CH₂CN; and R⁴ is hydrogen; or anindividual isomer or racemic or non-racemic mixture thereof.
 2. Acompound according to claim 1 wherein Q is ═C(R²⁴)—.
 3. A compoundaccording to claim 2 wherein —X—Y— is —CH₂—O—; R¹, R^(1.1), and R^(1.2)independently are selected from the group consisting of hydrogen,halogen, methyl, halogenmethyl, cyano, methoxy, and halogenmethoxy; R²¹,R²², and R²³ are hydrogen; and R³ is —C(O)N(H)CH₃.
 4. A compoundaccording to claim 1 wherein Q is ═N—.
 5. A compound of claim 1 whereinX—Y is —CH₂—O—.
 6. A compound according to claim 1 wherein R³ is—C(O)N(H)CH₃.
 7. A compound according to claim 1 wherein R³ is CH₂CN. 8.A compound according to claim 1 wherein X—Y is —CH₂—CH₂— or —CH═CH—. 9.A compound according to claim 1 wherein R²¹, R²², and R²³ are hydrogen.10. A compound according to claim 1 wherein R²¹ and R²³ are hydrogen andR²² is fluoro.
 11. A compound according to claim 1 wherein Q is ═CH—,═CF—, or ═C(CH₃)—.
 12. A compound according to claim 11 wherein Q is═CH—; X—Y is CH₂—O—; R²¹, R²², and R²³ are hydrogen; and R³ is—C(O)N(H)CH₃.
 13. A compound according to claim 12 wherein R¹, R^(1.1),and R^(1.2) independently are selected from the group consisting ofhydrogen, halogen, methyl, halogenmethyl, cyano, methoxy, andhalogenmethoxy.
 14. A compound according to claim 12 wherein R^(1.1) andR^(1.2) are hydrogen and R¹ is selected from fluoro, chloro,halogenmethyl, cyano, methoxy, and halogenmethoxy.
 15. A compoundaccording to claim 1 wherein R¹, R^(1.1) and R^(1.2) independently fromeach other are selected from the group consisting of hydrogen, halogen,methyl, halogenmethyl, cyano, methoxy or halogen-methoxy.
 16. A compoundaccording to claim 1 wherein R¹, R^(1.1), and R^(1.2) are halogen.
 17. Acompound according to claim 16 wherein R¹, R^(1.1), and R^(1.2) arefluoro.
 18. A compound according to claim 17 wherein R¹, R^(1.1), andR^(1.2) are 2,4,6-trifluoro; 2,4,5-trifluoro; 2,3,6-trifluoro;2,3,4-trifluoro; or 3,4,5-trifluoro.
 19. A compound according to claim 1wherein R^(1.2) is hydrogen and R¹ and R^(1.1) independently from eachother are selected from the group consisting of hydrogen, halogen,cyano, (C₁-C₆)-alkyl, halogen-(C₁-C₆)-alkyl, (C₁-C₆)-alkoxy orhalogen-(C₁-C₆)-alkoxy.
 20. A compound according to claim 19 wherein R¹and R^(1.1) independently are halogen or (C₁-C₆)-alkyl.
 21. A compoundaccording to claim 20 wherein R^(1.1) is halogen and R¹ is halogen or(C₁-C₆)-alkyl.
 22. A compound according to claim 1 wherein R¹, R^(1.1),and R^(1.2) are hydrogen.
 23. A compound according to claim 1 whereinR^(1.1) and R^(1.2) are hydrogen and R¹ is selected from halogen, cyano,(C₁-C₆)-alkyl, halogen-(C₁-C₆)-alkyl, (C₁-C₆)-alkoxy orhalogen-(C₁-C₆)-alkoxy.
 24. A compound according to claim 23 wherein R¹is halogen, methyl, halogenmethyl, cyano, methoxy, and halogenmethoxy.25. A compound according to claim 24 wherein R¹ is fluoro.
 26. Acompound according to claim 25 wherein R¹ is 3-fluoro or 4-fluoro.
 27. Acompound according to claim 24 wherein R¹ is chloro.
 28. A compoundaccording to claim 27 wherein R¹ is 3-chloro.
 29. A compound accordingto claim 24 wherein R¹ is halogenmethyl.
 30. A compound according toclaim 29 wherein R¹ is 3-trifluoromethyl.
 31. A compound according toclaim 24 wherein R¹ is cyano.
 32. A compound according to claim 24wherein R¹ is methoxy.
 33. A compound according to claim 32 wherein R¹is 2-methoxy, 3-methoxy, or 4-methoxy.
 34. A compound according to claim24 wherein R¹ is halogenmethoxy.
 35. A compound according to claim 34wherein R¹ is 3-trifluoromethoxy.
 36. A compound according to claim 1wherein the compound has (R)-configuration.
 37. A compound of theformula I*

wherein R¹ is halogen, halogen-(C₁-C₆)-alkyl, cyano, (C₁-C₆)-alkoxy orhalogen-(C₁-C₆)-alkoxy; R²¹, R²², R²′ and R²⁴ independently from eachother are selected from the group consisting of hydrogen and halogen; R³is —CONHR⁵, —CH₂CN or —CN; R⁴ is hydrogen; R⁵ is methyl; and n is 0, 1,2 or 3; as well as individual isomers, racemic or non-racemic mixturesthereof.
 38. A compound according to claim 37 wherein R³ is—C(O)N(H)CH₃.
 39. A compound according to claim 37 wherein R³ is CH₂CNand R⁴ is hydrogen.
 40. A compound according to claim 37 wherein n is 1or
 2. 41. A compound according to claim 37 wherein R¹ is halogen orhalogen (C₁-C₆)-alkyl.
 42. A compound according to claim 41 wherein R¹is fluoro, chloro, or trifluoromethyl.
 43. A compound selected from thegroup consisting of(RS)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,(RS)-[1-[4-(4-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,(RS)-1-[4-(3-chloro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,(RS)-[1-[4-(3,4-difluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,(RS)-[1-[4-(2,6-difluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,(RS)-5-oxo-1-[4-(2,4,6-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methylamide,(RS)-5-oxo-1-[4-(2,4,5-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methylamide,(RS)-5-oxo-1-[4-(2,3,6-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methylamide,(RS)-5-oxo-1-[4-(2,3,4-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methylamide, and(RS)-5-oxo-1-[4-(3,4,5-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methylamide.
 44. A compound selected from the group consisting of(RS)-1-[4-(5-fluoro-2-methyl-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,(RS)-1-[4-(3-methoxy-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,(RS)-1-[4-(2-methoxy-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,(RS)-5-oxo-1-[4-(3-trifluoromethoxy-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methylamide,(RS)-5-oxo-1-[4-(3-trifluoromethyl-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methylamide,(RS)-1-[4-(3-cyano-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,(RS)-1-[4-(3-fluoro-benzyloxy)-3-methyl-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,(RS)-1-[4-(4-fluoro-benzyloxy)-3-methyl-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,(RS)-1-[4-(3-chloro-benzyloxy)-3-methyl-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,(RS)-1-[3-fluoro-4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,(RS)-1-[2-fluoro-4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide, and(RS)-1-[2,5-difluoro-4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide.
 45. A compound selected from the group consisting of(RS)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acidmethylamide,(R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,(S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,(R)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acidmethylamide, (S)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylicacid methylamide,(R)-1-[4-(4-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,(R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide,(R)-1-[4-(3-chloro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide, and(R)-1-[4-(2,6-difluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide.
 46. A compound selected from the group consisting of(R)-5-oxo-1-[4-(2,4,6-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylicacid methylamide,(RS)-1-[4-(3,4-difluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetonitrile,(RS)-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetonitrile,(RS)-[1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidin-3-yl]-acetonitrile,(RS)-(E)-1-{4-[2-(3-fluoro-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methylamide,(RS)-(E)-1-{4-[2-(4-methoxy-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methylamide,(RS)-(E)-1-{4-[2-(3-methoxy-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methylamide, and(RS)-(E)-1-{4-[2-(4-fluoro-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methylamide.
 47. A compound selected from the group consisting of(RS)-1-{4-[2-(3-chloro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methylamide,(RS)-1-{4-[2-(4-chloro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methylamide,(RS)-1-{4-[2-(3-fluoro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methylamide,(RS)-1-{4-[2-(4-fluoro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methylamide,(RS)-1-{4-[2-(3-methoxy-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylicacid methylamide,(RS)-1-[6-(4-fluoro-benzyloxy)-pyridin-3-yl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide, and(RS)-1-[4-(2-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid methylamide.
 48. A composition comprising a compound of formula I

wherein Q is ═N— or ═C(R²⁴)—; X—Y is —CH₂—CH₂—, —CH═CH— or —CH₂—O—; R¹,R^(1.1) and R^(1.2) independently from each other are selected from thegroup consisting of hydrogen, halogen, (C₁-C₆)-alkyl,halogen-(C₁-C₆)-alkyl, cyano, (C₁-C₆)-alkoxy or halogen-(C₁-C₆)-alkoxy;R²¹, R²² and R²³ independently from each other are selected from thegroup consisting of hydrogen and halogen; R¹⁴ is hydrogen, halogen ormethyl; R³ is —C(O)N(H)CH₃ or —CH₂CN; and R⁴ is hydrogen; or anindividual isomer or racemic or non-racemic mixture thereof, and apharmaceutically acceptable carrier.
 49. A composition comprising acompound of formula I*

wherein R¹ is halogen, halogen-(C₁-C₆)-alkyl, cyano, (C₁-C₆)-alkoxy orhalogen-(C₁-C₆)-alkoxy; R²¹, R²², R²³ and R²⁴ independently from eachother are selected from the group consisting of hydrogen and halogen; R³is —CONHR⁵, —CH₂CN or —CN; R⁴ is hydrogen; R⁵ is methyl; and n is 0, 1,2 or 3; or an individual isomer or racemic or non-racemic mixturethereof, and a pharmaceutically acceptable carrier.
 50. A process forthe preparation of compounds of formula I according to claim 1 whereinR³ is —C(O)N(H)CH₃ comprising reacting a compound of formula II

wherein R¹, R^(1.1), R^(1.2), R²¹, R²², R²³, R⁴, —X—Y— and Q have themeanings as defined in claim 1 and R* is hydrogen or (C₁-C₆)-alkyl withan amine of formula H₂N—R⁵, wherein R⁵ has the meaning as defined inclaim
 1. 51. A process for the preparation of compounds of formula Iaccording to claim 1 wherein R³ is CH₂CN comprising reducing a compoundof formula II

wherein R¹, R^(1.1), R^(1.2), R²², R²³, R⁴, —X—Y— and Q have themeanings as defined in claim 1 and R* is hydrogen or (C₁-C₆)-alkyl to acompound of formula III

wherein R¹, R^(1.1), R²¹, R²¹, R²², R²³, R⁴, —X—Y— and Q have themeanings as defined in claim 1, and reacting the compound of formula IIIwith a cyanide salt.
 52. A method for the treatment of Alzheimer'sdisease comprising administering to an individual a therapeuticallyeffective amount of a compound of claim
 1. 53. A method for thetreatment of senile dementia comprising administering to an individual atherapeutically effective amount of a compound of claim 1.